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High Affinity Small Molecule C5a Receptor Modulators - PDF

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United States Patent: 6723743


































 
( 1 of 1 )



	United States Patent 
	6,723,743



 Thurkauf
,   et al.

 
April 20, 2004




 High affinity small molecule C5a receptor modulators



Abstract

This invention relates to low molecular weight, non-peptidic,
     non-peptidomimetic, organic molecules that act as modulators of mammalian
     complement C5a receptors, preferably ones that act as high affinity C5a
     receptor ligands and also to such ligands that act as antagonists or
     inverse agonists of complement C5a receptors, preferably human C5a
     receptors, Preferred compounds of the invention possess one or more, and
     preferably two or more, three or more, four or more, or all of the
     following properties in that they are; 1) multi-aryl in structure (having
     a plurality of un-fused or fused aryl groups), 2) heteroaryl in structure,
     3) orally available in vivo (such that a sub-lethal or preferably a
     pharmaceutically acceptable oral dose can provide a detectable in vitro
     effect such as a reduction of C5a-induced neutropenia), 4) comprised of
     fewer than four, preferably fewer than three, or fewer than two, or no
     amide bonds, and 5) capable of inhibiting leukocyte chemotaxis at
     nanomolar concentrations and preferably at sub-nanomolar concentrations.
     Specifically exemplified representative compounds include, but are not
     limited to optionally substituted arylimidazoles, optionally substituted
     arylpyridyls, optionally substituted aryl-substituted
     cycloalkylimidazoles, optionally substituted arylpyrazoles, optionally
     substituted benzimidazoles, optionally substituted aryl-substituted
     tetrahydroisoquinolines, and optionally substituted biaryl carboxamides.
     This invention also relates to pharmaceutical compositions comprising such
     compounds. It further relates to the use of such compounds in treating a
     variety of inflammatory and immune system disorders. Additionally, this
     invention relates to the use such compounds as probes for the localization
     of C5a receptors.


 
Inventors: 
 Thurkauf; Andrew (Danbury, CT), He; Xiao-shu (Branford, CT), Zhao; He (Branford, CT), Peterson; John (Madison, CT), Zhang; Xiaoyan (Bridgewater, NJ), Brodbeck; Robbin (Madison, CT), Krause; James (Madison, CT), Maynard; George (Clinton, CT), Hutchison; Alan (Madison, CT) 
 Assignee:


Neurogen Corporation
 (Branford, 
CT)





Appl. No.:
                    
 09/672,071
  
Filed:
                      
  September 28, 2000





  
Current U.S. Class:
  514/396  ; 514/397; 514/398; 514/400; 548/311.1; 548/312.4; 548/314.7; 548/315.1; 548/315.4; 548/316.4; 548/335.1; 548/335.5
  
Current International Class: 
  C07C 235/54&nbsp(20060101); C07C 235/60&nbsp(20060101); C07C 235/62&nbsp(20060101); C07C 233/11&nbsp(20060101); C07C 237/20&nbsp(20060101); C07C 233/78&nbsp(20060101); C07C 233/22&nbsp(20060101); C07C 235/00&nbsp(20060101); C07C 235/46&nbsp(20060101); C07C 235/48&nbsp(20060101); C07C 323/62&nbsp(20060101); C07C 233/73&nbsp(20060101); C07C 323/00&nbsp(20060101); C07C 233/00&nbsp(20060101); C07C 237/00&nbsp(20060101); C07C 235/66&nbsp(20060101); C07C 233/65&nbsp(20060101); C07C 233/66&nbsp(20060101); C07D 207/00&nbsp(20060101); C07D 235/00&nbsp(20060101); C07D 233/54&nbsp(20060101); C07D 235/18&nbsp(20060101); C07D 405/14&nbsp(20060101); C07D 405/06&nbsp(20060101); C07D 207/327&nbsp(20060101); C07D 405/00&nbsp(20060101); C07D 403/12&nbsp(20060101); C07D 235/14&nbsp(20060101); C07D 401/06&nbsp(20060101); C07D 401/12&nbsp(20060101); C07D 403/00&nbsp(20060101); C07D 471/04&nbsp(20060101); C07D 233/00&nbsp(20060101); C07D 233/68&nbsp(20060101); C07D 405/12&nbsp(20060101); C07D 235/02&nbsp(20060101); C07D 213/00&nbsp(20060101); C07D 215/00&nbsp(20060101); C07D 213/38&nbsp(20060101); C07D 213/82&nbsp(20060101); C07D 409/00&nbsp(20060101); C07D 317/00&nbsp(20060101); C07D 409/14&nbsp(20060101); C07D 215/12&nbsp(20060101); C07D 231/00&nbsp(20060101); C07D 471/00&nbsp(20060101); C07D 333/24&nbsp(20060101); C07D 409/12&nbsp(20060101); C07D 417/12&nbsp(20060101); C07D 217/04&nbsp(20060101); C07D 217/14&nbsp(20060101); C07D 317/58&nbsp(20060101); C07D 217/06&nbsp(20060101); C07D 333/28&nbsp(20060101); C07D 217/16&nbsp(20060101); C07D 417/00&nbsp(20060101); C07D 333/54&nbsp(20060101); C07D 217/00&nbsp(20060101); C07D 333/00&nbsp(20060101); C07D 231/12&nbsp(20060101); C07D 401/00&nbsp(20060101); A61K 031/415&nbsp(); C07D 233/02&nbsp(); C07D 231/02&nbsp(); C07D 403/02&nbsp(); C07D 233/61&nbsp()
  
Field of Search: 
  
  











 514/396,397,398,400 548/311.1,312.4,314.7,315.1,315.4,316.4,335.1,335.5
  

References Cited  [Referenced By]
U.S. Patent Documents
 
 
 
5159083
October 1992
Thurkauf et al.

5428164
June 1995
Thurkauf et al.

5478934
December 1995
Yuan et al.

5633376
May 1997
Thurkauf et al.

5633377
May 1997
Thurkauf et al.

5646280
July 1997
Thurkauf et al.

5681956
October 1997
Thurkauf et al.



 Foreign Patent Documents
 
 
 
WO 02/14265
Feb., 2002
WO



   
 Other References 

Database CA on STN, (Columbus, OH, USA), No. 128:3703, Thurkauf, et al. `Preparation of 4-aryl substituted piperazinylmethylphenyl imidazoles
as a new class of dopamine receptor subtype specific ligands`, abstract, Oct. 28, 1997.
.
Database CA on STN, (Columbus, OH, USA), No. 123:55767, Thurkauf et al. `2-Phenyl-4-(aminomethyl)imidazoles as potential antipsychotic agents. Synthesis and dopamine D2 receptor binding,` abstract, J. Med. Chem., vol. 38, No. 12, pp. 2251-2255,
1995.
.
Database CA on STN, (Columbus, OH, USA), No. 117: 2513500350, Thurkauf, etal., `Preparation of (aminomethyl)phenylimidazoles as dopamine receptor ligands,` abstract, Jul. 23, 1992.
.
Database CA on STN, (Columbus, OH, USA), No. 105:191381, Shiga, et al., `Silane derivatives,` abstract, Mar. 24, 1986.
.
Database CA on STN, (Columbus, OH, USA), No. 131:257737, He, et al., `Enantioselective total synthesis of aspidophytine,` abstract, J. Am. Chem. Soc., vol. 121, No. 28, pp. 6771-6772, 1999.
.
Drug Report for "C5a antagonists", Merck & Co., from the Investigational Drugs database, search done Feb. 18, 2002, last update Apr. 17, 2001. Summary, 1 page.
.
Shilcrat, et al, "A New Regioselective Synthesis of 1,2,5-Trisubstituted 1H-Imidazoles and its Application to the Development of Eprosartan", J. Org. Chem. 1997, 62, pp. 8449-8454.
.
S.E. de Laszlo, et al, "A Nonpeptidic Agonist Ligand of the Human C5A Receptor: Synthesis, Binding Affinity Optimization and Functional Characterization", Bioorganic & Medicinal Chemistry Letters, vol. 7 No. 2, pp. 213-218, and
907-912.1997,.COPYRGT. 1997 Elsevier Science Ltd..  
  Primary Examiner:  Seaman; D. Margaret


  Attorney, Agent or Firm: Horvath; Leslie Anne
Fidel; Seth
    Edwards & Angell, LLP



Parent Case Text



This application claims priority from the following five U.S. Provisional
     applications: 1) application No. 60/156,390, filed Sep. 28, 1999; 2)
     application No. 60/202,749, filed May 8, 2000; 3) application No.
     60/212,449, filed Jun. 16, 2000; 4) application No. 60/221,787, filed Jul.
     31, 2000; and 5) application No. 60/224,036, filed Aug. 9, 2000, all of
     which five applications which are incorporated herein by reference for
     their teachings with regard to C5a receptor ligands, including
     arylimidazoles, arylpyridyls, aryl-substituted cycloalkylimidazoles,
     arylpyrazoles, and benzimidazoles.

Claims  

What is claimed is:

1.  A compound of the formula: ##STR8001##


or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, or 2;  R.sub.1 is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group
having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;  R.sub.2 is chosen from optionally substituted C.sub.1 -C.sub.8 alkyl, optionally substituted C.sub.3 -C.sub.8 cycloalkyl, optionally substituted C.sub.3 -C.sub.8
cycloalkyl(C.sub.1 -C.sub.8)alkyl, optionally substituted C.sub.2 -C.sub.8 alkenyl, optionally substituted C.sub.2 -C.sub.8 alkynyl, haloalkyl, aminoalkyl, each of which may be unsubstituted or substituted with one or more substituents selected from oxo,
hydroxy, alkoxy, amide, ester, cyano, acetoxy or nitro;  R.sub.3, R.sub.3A, R.sub.5, and R.sub.6 are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl;  R.sub.4 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally
substituted;  or R.sub.4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;  Ar.sub.1
is optionally substituted carbocyclic aryl or optionally substituted arylalkyl;  and R.sub.A represents 0 to 3 groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6
alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


2.  A compound that is: 1-(1-butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenyl methyl])aminomethylimidazole;  1-(1-butyl)-2-phenyl-5-(1-[N-{3,4-methylenedioxyphenylmethyl}-N-phenylmethy l]amino)ethylimidazole; 
1-(1-Butyl)-2-phenyl-4-methyl-5-(N-[3,4-methylenedioxyphenyl-methyl]-N-phen ylmethyl)aminomethylimidazole;  1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phen ylmethyl)aminomethylimidazole; 
1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phen ylmethyl)aminomethylimidazole;  1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phe nylmethyl) aminomethylimidazole; 
1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])a minomethylimidazole;  1-(1-Butyl)-2-(2-methylphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phen ylmethyl)aminomethylimidazole; 
1-(1-Butyl)-2-(4-fluorophenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])am inomethylimidazole;  1-(1-Butyl)-2-(2-methylphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])am ino-methylimidazole; 
1-(1-Butyl)-2-(3-fluorophenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])am inomethylimidazole;  1-(1-Butyl)-2-(3-methoxyphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phe nylmethyl)-aminomethylimidazole; 
1-(1-Butyl)-2-phenyl-5-{1-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethy l)amino}ethylimidazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dichlorop henyl]methyl)aminomethylimidazole; 
1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenylmethyl])aminomethyli midazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-methoxyph enylmethyl])-aminomethylimidazole; 
1-(1-Butyl)-2-phenyl-5-N-[3,4-methylenedioxyphenylmethyl]-N-[4-{1-propyl}ph enylmethyl])aminomethylimidazole;  1-(1-Butyl)-2-phenyl-5-N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dichloroph enylethyl])aminomethylimidazole; 
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[4-nitrophenyl methyl])aminomethylimidazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{1-propylox y}phenylmethyl])aninomethylimidazole; 
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[quinol-6-ylme thyl])-aminomethylimidazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2,3-dichlorop henylmethyl])-aminomethylimidazole; 
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dimethylp henylmethyl])-aminomethylimidazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[indan-2-yl])- aminomethylimidazole; 
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2-phenylethyl ])aminomethylimidazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)a minomethyl-imidazole; 
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-ethyl)aminomet hylimidazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-propyl])ami nomethyl-imidazole; 
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-butyl])amin omethyl-imidazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cycloheptylmet hyl)amino-methylimidazole; 
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-isobutyl)amino methyl-imidazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2-cyclopentyl ethyl])amino-methylimidazole; 
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3-cyclopentyl propyl])amino-methylimidazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-n-octyl])am inomethyl-imidazole; 
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclopropylmet hyl)amino-methylimidazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclopentylmet hyl)amino-methylimidazole; 
1-(1-Butyl)-2-phenyl-5-N-[3,4-methylenedioxyphenylmethyl]-N-cyclohexylmethy l)amino-methylimidazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[t-amyl])amino methylimidazole; 
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-{3-methyl}b utyl)]amino-methylimidazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-{2,2-dimeth yl}butyl]) aminomethylimidazole; 
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-methyl)aminome thylimidazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylnethyl]-N-[2-thiophenylm ethyl])amino-methylimidazole; 
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[indol-5-ylmet hyl])amino-methylimidazole;  1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylendioxyphenylmethyl]-N-[{1-methylindol -5-yl}methyl])aminomethylimidazole; 
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[4-hydroxy-2-c hlorophenyl]-methyl)aminomethylimidazole;  1-(1-Butyl)-2-(3-fluorophenyl)-5-(1-[N-{2-chloro-4-hydroxyphenyl}methyl-N-p henylmethyl])aminoethylimidazole; 
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[2,3-dihydrobe nzo[b]furan-5-yl]methyl)aminomethylimidazole;  1-Butyl-2-(4-fluorophenyl)-5-(1-[N-{3,4-methylenedioxyphenyl}methyl-N-pheny lmethyl]-amino)ethylimidazole; 
1-(1-Butyl)-2-phenyl-5-(N-phenylmethyl-N-[3,4-dimethoxyphenylmethyl])aminom ethylimidazole;  1-(1-Butyl)-2-phenyl-5-(N-[6-chloro-3,4-methylenedioxyphenylmethyl]-N-pheny lmethyl)-aminomethylimidazole; 
Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethy l)-amine;  Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-5-(4-methoxy-phenyl)-2-phenyl-3 H-imidazol-4-ylmethyl]-amine; 
Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl-3 H-imidazol-4-ylmethyl)]-amine;  Benzo[1,3]dioxol-5-ylmethyl-benzyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-y l)-pentyl]-amine; 
Benzo[1,3]dioxol-5-ylmethyl-benzyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-y l)-ethyl]-amine;  Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-5-(4-fluoro-phenyl)-2-phenyl-3H -imidazol-4-ylmethyl]-amine; 
4-{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-2,4-diphenyl-imidazol -1-yl}-butan-1-ol;  1-(1-Butyl)-2-(4-fluorophenyl)-5-(1-N,N-di[3,4-methylenedioxyphenylmethyl]a mino)ethylimidazole;


or a pharmaceutically acceptable salt, prodrug or hydrate thereof.


3.  A pharmaceutical composition comprising a compound of claim 1 or a prodrug or hydrate thereof and a pharmaceutically acceptable carrier therefor.


4.  A method for treating a patient suffering from rheumatoid arthritis, psoriasis or bronchial asthma comprising administering to the patient an effective amount of a compound or composition of claim 1.


5.  A method for treating a patient suffering from Alzheimer's disease, myocardial infarction or artherosclerosis comprising administering to the patient an effective amount of a compound or composition of claim 1.


6.  A compound according to claim 1 of the formula: ##STR8002##


wherein R.sub.A, Ar.sub.1, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are as defined in clam 1.


7.  A compound according to claim 1 of the formula: ##STR8003##


wherein: R.sub.1 is hydrogen, C.sub.1 -C.sub.7 alkyl, halogen or phenyl optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, halogen, hydroxy, amino, or mono- or di(C.sub.1 -C.sub.6)alkylamino;  R.sub.2 is C.sub.1 -C.sub.8
alkyl or C.sub.3 -C.sub.8 cycloalkyl;  and R.sub.3 is hydrogen or C.sub.1 -C.sub.7 alkyl.


8.  A compound according to claim 1 of the formula: ##STR8004##


wherein: Ar.sub.1 is phenyl which is optionally substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6
alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;  R.sub.1 is hydrogen, C.sub.1 -C.sub.7 alkyl, halogen or phenyl optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy,
halogen, hydroxy, amino, or mono- or di(C.sub.1 -C.sub.6)alkylamino;  R.sub.2 is C.sub.1 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl;  and R.sub.3 is hydrogen or C.sub.1 -C.sub.7 alkyl;  and R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8
cycloalkyl, or (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which is unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1
-C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


9.  A compound according to claim 1 of the formula: ##STR8005##


wherein: Ar.sub.1 is phenyl which is optionally substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6
alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;  R.sub.1 is hydrogen, C.sub.1 -C.sub.7 alkyl, halogen or phenyl optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy,
halogen, hydroxy, amino, or mono- or di(C.sub.1 -C.sub.6)alkylamino;  R.sub.2 is C.sub.1 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl;  and R.sub.3 is hydrogen or C.sub.1 -C.sub.7 alkyl;  and R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl,
pyridyl, or pyrimidyl, each of which is optionally substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl,
C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;  or R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR8006## wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro,
cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


10.  A compound according to claim 1 of the formula: ##STR8007##


wherein: Ar.sub.1 is phenyl which is optionally substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6
alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;  R.sub.1 is hydrogen, methyl, ethyl, or phenyl;  R.sub.2 is C.sub.3 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl;  and R.sub.3 is hydrogen or
methyl;  and R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl, or (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


11.  A compound according to claim 1 of the formula: ##STR8008##


wherein: Ar.sub.1 is phenyl which is optionally substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6
alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;  R.sub.1 is hydrogen, methyl, ethyl, or phenyl;  R.sub.2 is C.sub.3 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl;  and R.sub.3 is hydrogen or
methyl;  and R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, or pyrimidyl each of which is optionally substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,
hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;  or R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR8009##
wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and
mono- or di(C.sub.1 -C.sub.6)alkylamino.


12.  A compound according to claim 1 of the formula: ##STR8010##


or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: Ar.sub.1 is phenyl which is optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl,
trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;  R.sub.1 is selected from i) hydrogen, halogen,
hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, haloalkyl, and ii) C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, and (C.sub.3 -C.sub.8)cycloalkyl)
C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;  or R.sub.1 is
selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or substituted with up
to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or
di(C.sub.1 -C.sub.6)alkylamino;  R.sub.2 and R.sub.3 are independently selected from i) hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, haloalkyl, and ii) C.sub.1 -C.sub.8 alkyl, C.sub.2
-C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, and (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl,
trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;  and R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3
-C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;  or R.sub.4 is phenyl, thienyl, pyridyl, or pyrimidyl, each of which is optionally substituted with up to four groups
independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1
-C.sub.6)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl;  or R.sub.4 is a bicyclic
oxygen-containing group of the formula: ##STR8011## wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


13.  A compound according to claim 12, wherein the compound exhibits an IC.sub.50 of 1 uM or less in an assay of C5a mediated chemotaxis or calcium mobilization.


14.  A compound according to claim 12, wherein: R.sub.1 is hydrogen, methyl, ethyl, or phenyl;  R.sub.2 is C.sub.3 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl;  R.sub.3 is hydrogen or methyl;  and R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.2
-C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, and (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


15.  A compound according to claim 12, wherein: R.sub.1 is hydrogen, methyl, ethyl, or phenyl;  R.sub.2 is C.sub.3 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl;  R.sub.3 is hydrogen or methyl;  and R.sub.4 is phenyl, phenyl(C.sub.1
-C.sub.4)alkyl, thienyl, pyridyl, or pyrimidyl, each of which is optionally substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


16.  A compound according to claim 12, wherein: R.sub.1 is hydrogen, methyl, ethyl, or phenyl;  R.sub.2 is C.sub.3 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl;  R.sub.3 is hydrogen or methyl;  and R.sub.4 is a bicyclic oxygen-containing group
of the formula: ##STR8012## wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1
-C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


17.  A compound according to claim 12 in which Ar.sub.1 is phenyl, R.sub.1 is hydrogen, R.sub.2 is phenyl, R.sub.3 is hydrogen, R.sub.4 is phenyl, and Ar.sub.2 is benzo[1,3]dioxol-5-yl.


18.  A compound according to claim 1 which has the formula ##STR8013##


wherein Ar.sub.1, R.sub.2, and R.sub.4 are defined as follows:


19.  A compound according to claim 1 which has the formula ##STR8014##


wherein R.sub.4 is cyclobutyl-methyl, pentyl, hexyl, 4-methyl-pentyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, heptyl, cyclohexyl-ethyl, 2-phenyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl, 2-methyl-benzyl, 3-fluoro-benzyl, 4-fluoro-benzyl,
2-fluoro-benzyl, 4-ethyl-benzyl, 3,5-dimethyl-benzyl, 2,3-dimethyl-benzyl, 2,5-dimethyl-benzyl, 2,4-dimethyl-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 2-methoxy-benzyl, 3-fluoro-4-methyl-benzyl, 2-methyl-3-fluoro-benzyl, 2-methyl-5-fluoro-benzyl,
3-chloro-benzyl, 4-chloro-benzyl, 2-chloro-benzyl, 3,4-difluoro-benzyl, 2,3-difluoro-benzyl, 2,5-difluoro-benzyl, 2,4-difluoro-benzyl, 4-isopropyl-benzyl, 3-ethoxy-benzyl, 4-ethoxy-benzyl, 2-ethoxy-benzyl, phenyl-ethyl, naphth-1-yl-methyl,
4-methylsulfanyl-benzyl, 3-fluoro-4-methoxy-benzyl, 3-methyl-4-chloro-benzyl, 3-chloro-4-fluoro-benzyl, 4-butyl-benzyl, 4-tert-butyl-benzyl, 4-propoxy-benzyl, 4-isopropoxy-benzyl, 4-ethylsulfanyl-benzyl, 2,3,5,6-tetrafluoro-benzyl,
2,4,6-trifluoro-benzyl, 2,3,6-trifluoro-benzyl, 2-chloro-6-fluoro-benzyl, 2,4-dimethoxy-phenyl-ethyl, 2,6-difluoro-phenyl-ethyl, 4-methylsulfanyl-phenyl-ethyl, benzo[1,3]dioxol-5-ylethyl, 2-chloro-5-methylsulfanyl-benzyl, 2-bromo-5-methyl-benzyl,
2-bromo-3-methyl-benzyl, 2-chloro-5-trifluoromethyl-benzyl, 2-methylsulfanyl-benzyl, 2-bromo-3,4-dimethoxy-phenyl-ethyl, 2-methoxy-5-bromo-phenyl-ethyl, 2,3-dimethoxy-phenyl-ethyl, 2,3-difluoro-phenyl-ethyl, 3-iodo-4-methyl-benzyl, 4-iodo-phenyl-ethyl,
thiophen-2-yl-methyl, 4-methyl-phenyl-ethyl, 2-methyl-phenyl-ethyl, 2-phenyl-propyl, 2-fluoro-phenyl-ethyl, 2-phenyl-butyl, 2-o-tolyl-propyl,  3-methoxy-phenyl-ethyl, 4-methoxy-phenyl-ethyl, 4-ethoxy-phenyl-ethyl, 2-ethoxy-phenyl-ethyl,
3-chloro-phenyl-ethyl, 2-(4-methoxy-phenyl)butyl, 2,5-dimethoxy-phenyl-ethyl, 4-trifluoromethyl-phenyl-ethyl, 2,4-dichloro-phenyl-ethyl, 3-bromo-phenyl-ethyl, 4-bromo-phenyl-ethyl, 2-bromo-phenyl-ethyl, 2,3-dimethoxy-benzyl, 2,5-dimethoxy-benzyl,
2-methoxy-4-chloro-benzyl, 3-bromo-4-methyl-benzyl, 3-bromo-4-fluoro-benzyl, 3-iodo-benzyl, or 4-iodo-benzyl, or 2-iodo-benzyl.


20.  A compound according to claim 1 which has the formula ##STR8015##


wherein R.sub.4 is butyl, iso-butyl, cyclobutyl-methyl, 3-methyl-butyl, 2,2-dimethyl-propyl, cyclopentyl-methyl, hexyl, 2-methyl-pentyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, 2,2-dimethyl-butyl, cyclopentyl-ethyl, cyclohexyl-methyl, heptanyl,
cyclohexyl-ethyl, cycloheptyl-methyl, cyclopentyl-propyl, octyl, 3-methyl-benzyl, 4-methyl-benzyl, 2-fluoro-phenyl, 3,4-dimethyl-benzyl, 2,3-dimethyl-benzyl, benzo[1,3]dioxol-5-ylmethyl, methyl-sulfanyl-benzyl, 3,5-dimethoxy-benzyl, 2,5-dimethoxy-benzyl,
2,5-dichloro-benzyl, 3-bromo-benzyl, 4-bromo-benzyl, 2-bromo-benzyl, 2-phenyl-ethyl-benzyl, 2,4,6-trifluoro-benzyl, 2,3,6-trifluoro-benzyl, 3,4-dimethoxy-phenyl-ethyl, benzo[1,3]dioxol-5-ylethyl, naphtha-2-yl-ethyl, 4-methyl-phenyl-ethyl,
3-methoxy-phenyl-ethyl, 4-methoxy-phenyl-ethyl, 4-chloro-phenyl-ethyl, 4-iodo-phenyl-ethyl, 4-bromo-phenyl-ethyl, 4-methylsulfanyl-phenyl-ethyl, 2,6-difluoro-benzyl, 2-methylsulfanyl-benzyl, 2-trifluoromethoxy-benzyl,
2,5-di-(2,2,2-trifluoro-ethoxy)-benzyl, 2-bromo-3-methyl-benzyl, 2-chloro-5-methylsulfanyl-benzyl, napth-1-yl-methyl, or 9H-fluoren-3-yl-methyl.


21.  A compound according to claim 1 which has the formula ##STR8016##


wherein R.sub.4 is 2-ethyl-butyl, 2,2-dimethyl-butyl, cyclopentylethyl, cyclohexylmethyl, heptanyl, 3-methyl-butyl, benzo[1,3]dioxol-5-ylmethyl, 4-methylsulfanyl-benyl, 2,5-dimethoxy-benzyl, 2,4-dimethoxy-benzyl, 3-methoxy-phenyl-ethyl,
4-methoxy-phenyl-ethyl, 4-iodo-phenyl-ethyl, 4-methylsulfanyl-ethyl, 2-methylsulfanyl-benzyl, 2,3-dihydro-benzofuran-5-ylmethyl, 3,4-dimethoxy-phenyl-ethyl, 3-methoxy-4-ethoxy-phenyl-ethyl, or napth-2-yl-ethyl.


22.  A compound according to claim 1 which has the formula ##STR8017##


wherein R.sub.4 is naphth-2-yl-methyl, 3-chloro-4-methyl-benzyl, 2,3-dihydro-benzofuran-5-ylmethyl, 4-difluoromethoxy-benzyl, 2-fluoro-phenyl-ethyl, 2-methoxy-phenyl-ethyl, 2-ethoxy-phenyl-ethyl, 2-bromo-phenyl-ethyl, 2,5-dimethoxy-phenyl-ethyl,
2,3-dimethoxy-phenyl-ethyl, 2,4-dimethoxy-phenyl-ethyl, or 2-allylsulfanyl-pyridin-3-ylmethyl.


23.  A compound according to claim 1 which has the formula ##STR8018##


wherein Ar.sub.1, R.sub.1 and R.sub.4 are defined, as follows:


24.  A compound according to claim 1 which has the formula ##STR8019##


wherein Ar.sub.1, R.sub.3, and R.sub.4 arc define, as follows:


25.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is phenyl, R.sub.2 is butyl, R.sub.3 is hydrogen, and R.sub.4 is propyl.


26.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is phenyl, R.sub.2 is butyl, R.sub.3 is hydrogen, and R.sub.4 is phenyl.


27.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is tert-butyl, R.sub.2 is butyl, R.sub.3 is hydrogen, and R.sub.4 is phenyl.


28.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is tert-butyl, R.sub.2 is butyl, R.sub.3 is hydrogen, and R.sub.4 is benzo[1,3]dioxol-5-yl.


29.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is tert-butyl, R.sub.2 is butyl, R.sub.3 is hydrogen, and R.sub.4 is 2-chloro-4-hydroxy-phenyl.


30.  A compound according to claim 9 wherein Ar.sub.1 is phenyl R.sub.1 is tert-butyl, R.sub.2 is butyl, R.sub.3 is hydrogen, and R.sub.4 is 3-chloro-4-hydroxy-phenyl.


31.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is 4-methoxy-phenyl, R.sub.2 is butyl, R.sub.3 is hydrogen, and R.sub.4 is propyl.


32.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is 4-fluoro-phenyl, R.sub.2 is butyl, R.sub.3 is hydrogen, and R.sub.4 is propyl.


33.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is 4-fluoro-phenyl, R.sub.2 is butyl, R.sub.3 is hydrogen, and R.sub.4 is phenyl.


34.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is phenyl, R.sub.2 is butyl, R.sub.3 is hydrogen, and R.sub.4 is benzo[1,3]dioxol-5-yl.


35.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is phenyl, R.sub.2 is butyl, R.sub.3 is hydrogen, and R.sub.4 is 4-acetoxy-phenyl.


36.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is phenyl, R.sub.2 is butyl, R.sub.3 is hydrogen, and 4-carboxy-phenyl.


37.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is phenyl, R.sub.2 is butyl, R.sub.3 is butyl, and R.sub.4 is phenyl.


38.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is phenyl, R.sub.2 is butyl, R.sub.3 is methyl and R.sub.4 is phenyl.


39.  A compound of the formula ##STR8020##


wherein Ar.sub.1, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are define, as follows:


40.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is phenyl, R.sub.2 is butyl, R.sub.3 is methyl, and R.sub.4 is 4-carboxy-phenyl.


41.  A compound according to claim 9 wherein Ar.sub.1 is phenyl, R.sub.1 is phenyl, R.sub.2 is propyl, R.sub.3 is hydrogen, and R.sub.4 is 4-amino-sulfonyl-phenyl.


42.  A compound according to claim 1 which is represented by the formula: ##STR8028##


43.  A compound of the formula ##STR8029##


wherein R.sub.4 is ethyl, propyl, or butyl.


44.  A compound according to claim 1 which has the formula ##STR8030##


wherein R.sub.1 is phenyl;  R.sub.2 is ethyl, propyl, or pentyl, and R.sub.4 is butyl.  Description  

BACKGROUND


1.  Field of the Invention


This invention relates to low molecular weight, non-peptidic, non-peptidomimetic, organic molecules that act as modulators of mammalian complement C5a receptors, preferably ones that act as high affinity C5a recptor ligands.  The invention also
relates to such ligands that act as antagonists (including inverse agonists) of complement C5a receptors, preferably human C5a receptors.  This invention also relates to pharmaceutical compositions comprising such compounds.  It further relates to the
use of such compounds in treating a variety of inflammatory and immune system disorders.  Additionally, this invention relates to the use such compounds as probes for the localization of C5a receptors.


2.  Background of the Invention


C5a, a 74 amino acid peptide, is generated in the complement cascade by the cleavage of the complement protein C5 by the complement C5 convertase enzyme.  C5a has both anaphylatoxic (e.g., bronchoconstricting and vascular spasmogenic) and
chemotactic effects.  Therefore, it is active in engendering both the vascular and cellular phases of inflammatory responses.  Because it is a plasma protein and, therefore, generally almost instantly available at a site of an inciting stimulus, it is a
key mediator in terms of initiating the complex series of events that results in augmentation and amplification of an initial inflammatory stimulus.  The anaphylatoxic and chemotactic effects of the C5a peptide are believed to be mediated through its
interation with the C5a receptor (CD88 antigen), a 52 kD membrane bound G-protein coupled receptor (GPCR).  C5a is a potent chemoattractant for polymorphonuclear leukocytes, bringing neutrophils, basophils, eosinophils and monocytes to sites of
inflammation and/or cellular injury.  C5a is one of the most potent chemotactic agents known for a wide variety of inflammatory cell types.  C5a also "primes" or prepares neutrophils for various antibacterial functions, e.g., phagocytosis.  Additionally,
C5a stimulates the release of inflammatory mediators (e.g., histamines, TNF-.alpha., IL-1, IL-6, IL-8, prostaglandins, and leukotrienes) and the release of lysosomal enzymes and other cytotoxic components from granulocytes.  Among its other actions, C5a
also promotes the production of activated oxygen radicals and the contraction of smooth muscle.


Considerable experimental evidence implicates increased levels of C5a in a number of autoimmune diseases and inflammatory and related disorders.


Antagonists that block the binding of C5a to its receptor or other agents, including inverse agonists, which modulate signal transduction associated with C5a-receptor interactions, can inhibit the pathogenic events, including chemotaxis,
associated with anaphylatoxin activity contributing to such inflammatory and autoimmune conditions.  Despite many attempts, no one has previously been able to provide any small molecule (less than 700 Daltons MW, or amu) non-peptide, non-peptidomimetic,
non-peptoid, C5a antagonist that is essentially free of agonist activity at the C5a receptor and that exhibits a binding affinity for the C5a receptor of less than 1 micromolar, and preferably less than 100 nanomolar.


DESCRIPTION OF RELATED ART


Certain modified C5a peptides (i.e., modifications of C5a) have been identified as partial C5a antagonists and have been shown to block a number of C5a mediated actions including neutrophil chemotaxis, neutropenia and superoxide formation. 
Various C5a peptidomimetic compounds have also been reported as modulating C5a activity, including cyclic peptoids (a peptoid is a peptidomimetic compound comprising an oligomeric assemblage of naturally occurring amino acids that have been
N-substituted).  Typically these C5a modulatory compounds exhibit a molecular weight greater than 500 Daltons, and generally greater than 700 Daltons.


SUMMARY OF THE INVENTION


The present invention provides novel compounds that are small molecule C5a receptor antagonists that are non-peptide, non-peptidomimetic, and are preferably free of C5a receptor agonist activity, which compounds exhibit high affinity for the C5a
receptor, i.e., an affinity constant for binding to the C5a receptor of less than 1 micromolar.  Highly preferred compounds exhibit very high affinity for the C5a receptor, i.e., an affinity constant for binding to the C5a receptor of less than 100
nanomolar.


Preferred compounds are C5a receptor antagonists (including inverse agonists).


Preferred antagonists exhibit an antagonist EC.sub.50 (which as usd herein includes IC.sub.50) of less than 1 micromolar, preferably less than 100 nanomolar, in an assay of C5a mediated chemotaxis.  Preferred C5a receptors are mammalian,
preferably primate receptors, including human C5a receptors, and may either be cloned, recombinantly expressed receptors or naturally expressed receptors.  In certain preferred embodiments, compounds of the invention exhibit an affinity for human C5a
receptors that is higher than for rodent C5a receptors, preferably at least five times higher, more preferably ten times higher.


The compounds of the present invention do not interact with dopamine receptors with even moderate affinity, i.e., they do not bind to dopamine receptors with K.sub.i values of less than 100 micromolar.  Preferred compounds of the invention do not
bind to any naturally occurring receptors other than C5a receptors with high affinity, and preferably they do not bind to any naturally occurring receptors other than C5a receptors with even moderate affinity.


In certain embodiments these compounds also possess one or more, and preferably two or more, three or more, four or more, or all of the following properties in that they are: 1) multi-aryl in structure (having a plurality of un-fused or fused
aryl groups), 2) heteroaryl in structure, 3) orally available in vivo (such that a sub-lethal or preferably a pharmaceutically acceptable oral dose can provide a detectable in vivo effect such as a reduction of C5a-induced neutropenia), 4) comprised of
fewer than four, preferably fewer than three, or fewer than two, or no amide bonds, and 5) capable of inhibiting leukocyte chemotaxis at nanomolar concentrations and preferably at sub-nanomolar concentrations.


In a highly preferred aspect, the invention provides non-peptidic, non-peptidomimetic, low molecular weight compounds that act as high affinity antagonists of the human C5a receptor.  Specifically exemplified representative compounds include, but
are not limited to optionally substituted arylimidazoles (i.e. imidazoles having one or more ring substituents of optionally substituted carbocyclic aryl or optionally substituted heteroaryl), optionally substituted arylpyridyls (i.e. pyridyls having one
or more ring substituents of optionally substituted carbocyclic aryl or optionally substituted heteroaryl), optionally substituted aryl-substituted cycloalkylimidazoles (i.e. cycloalkylimidazoles having one or more ring substituents of optionally
substituted carbocyclic aryl or optionally substituted heteroaryl), optionally substituted arylpyrazoles (i.e. pyrazoles having one or more ring substituents of optionally substituted carbocyclic aryl or optionally substituted heteroaryl), optionally
substituted benzimidazoles, optionally substituted aryl-substituted tetrahydroisoquinolines (i.e. tetrahydroisoquinolines having one or more ring substituents of optionally substituted carbocyclic aryl or optionally substituted heteroaryl), and
optionally substituted biaryl carboxamides (i.e. a carboxamide that has one or more optionally substituted bi-carboxylic aryl or heteroaryl substituents).  Novel intermediates useful for synthesizing compounds of the invention are also provided.


Preferred compounds of the invention are compounds of Formula I, shown below, that bind specifically, and preferably with high affinity, to C5a receptors.


The invention also provides pharmaceutical compositions comprising compounds of the invention, including those of Formula I, including otppinally substituted arylimidazoles, optionally substituted arylpyridyls, optionally substituted
aryl-substituted cycloalkylimidazoles, optionally substituted arylpyrazoles, optionally substituted benzimidazoles, optionally substituted aryl-substituted tetrahydroisoquinolines, and optionally substituted biaryl carboxamides.  The C5a receptor
antagonist compounds described herein are particularly useful in the treatment of C5a-mediated inflammation, e.g., inflammation associated with various inflammatory and immune system disorders.  The invention further comprises a method of treating a
patient in need of such anti-inflammatory treatment or immune treatment an effective amount of a compound of the invention, e.g. an amount of a compound of the invention sufficient to yield a plasma concentration of the compound (or its active
metabolite, if a pro-drug) high enough to inhibit white blood cell (e.g., neutrophil) chemotaxis in vitro.  Treatment of humans, domesticated companion animals (pets) or livestock animals suffering such conditions with an effective amount of a compound
of the invention is contemplated by the invention.  For treating non-human animals of any particular species, a compound exhibiting high affinity for the C5a receptor of that particular species is preferred.


In a separate aspect, the invention provides methods of using compounds of the invention as positive controls in assays for receptor activity and using appropriately labeled compounds of the invention as probes for the localization of receptors,
particularly C5a receptors, e.g., in tissue sections (e.g., via autoradiography) or in vivo (e.g., via positron emission tomography, PET, or single positron emission computed tomography, SPECT, scanning and imaging).


The invention provides compounds and compositions that are useful as inhibitors of C5a-mediated chemotaxis (e.g., they may be used as standards in assays of such chemotaxis).  The invention additionally comprises methods of inhibiting
C5a-mediated cellular chemotaxis, preferably leukocyte (e.g., neutrophil) chemotaxis.  These methods comprise contacting white blood cells, particularly primate white blood cells, especially human white blood cells, with one or more compounds of the
invention.  Preferably the concentration is sufficient to inhibit chemotaxis of white blood cells in an in vitro chemotaxis assay, so that the levels of chemotaxis observed in a control assay (e.g., one to which a compound of the invention has not been
added) are significantly higher (significantly here measured as p.ltoreq.0.05 using a conventional parametric statistical analysis method such as a student's T-test) than the levels observed in an assay to which a compound of the invention has been
added.


Accordingly, a broad aspect of the invention is directed to non-peptidic organic (carbon-containing) molecules, having a molecular mass of less than 700 amu, that exhibit C5a antagonist activity or C5a inverse agonist activity with an EC.sub.50
of less than 500 nM in an assay of C5a mediated leukocyte chemotaxis.


More particularly the invention includes compounds of Formula I, ##STR1##


wherein: AR1 and AR2 are independently carbocyclic aryl or heteroaryl; LIP represents an alkyl, carbocyclic aryl, heteroaryl, or arylalkyl; A is oxygen or nitrogen; d.sub.1 represents the distance between A and the geometric center of AR1 and is
between 3 and 6 angstroms in at least one energetically accessible conformer of the compound; d.sub.2 represents the distance between A and the geometric center of AR2 and is between 5 and 10 angstroms in at least one energetically accessible conformer
of the compound; and d.sub.3 represents the distance between A and the nearest atom of LIP and is between 3 and 6 angstroms in at least one energetically accessible conformer of the compound.


Preferred compounds of Formula I exhibit antagonist (including inverse agonist) activity at C5a Receptors, and essentially no or little agonist activity at this receptor.  Preferably such compounds contain one or more heteroaryl rings.


Preferred compounds of the invention exhibit good activity in standard in vitro C5 receptor mediated chemotaxis assay, specifically the assay as specified in Example 12, which follows and is defined below.  Alternative preferred assays include
the calcium mobilization assay.  Preferred compounds of the invention exhibit an EC.sub.50 of about 500 nM or less in such a standard C5a mediated chemotaxis assay, more preferably an EC.sub.50 of about 200 nM or less in such a standard C5a mediated
chemotaxis assay, still more preferably an EC.sub.50 of about 100, 50, 25 and 10 nM in such a standard C5a mediated chemotaxis assay, even more preferably an EC.sub.50 of about 5 nM in such a standard C5a mediated chemotaxis assay.


The invention includes additional methods such as methods for localizing C5a recerptors in tissue section samples, comprising cotacting a tissue sample with detectably labelled one or more compounds of the invention that are preferably detectably
labeled, optionally washing the contacted tissue sample, and detecting the bound compound associated with the tissue sample.  Suitable detectable labels include e.g. .sup.125 I, tritium, .sup.32 P, .sup.99 Tc or the like.  A variety of detection methods
could be employed include single emission photono computed tomography ("SPECT").


Other aspects of the invention are discussed infra. 

BRIEF DESCRIPTION OF THE DRAWINGS


FIG. 1 is the sequence of SEQ ID NO-1. 

DETAILED DESCRIPTION OF THE INVENTION


Preferred compounds of the invention include carbon-containing molecules that comprise:


i) having a molecular mass of less than 700 amu;


ii) that is nonpeptidic;


iii) that exhibits C5a antagonist activity or C5a inverse agonist activity with an EC.sub.50 of less than 500 nM in an assay of C5a mediated leukocyte chemotaxis; and


iv) exhibits less than 10% intrinsic agonist activity in an assay of leukocyte chemotaxis.


Among such compounds, particularly preferred are those that contain one or more heteroaryl and/or carbocyclic rings.  For example, preferred are compounds of the following formula: ##STR2##


AR1 and AR2 are independently optionally substituted carbocyclic aryl or optionally substituted heteroaryl;


LIP represents an optionally substituted alkyl, optionally substituted carbocyclic aryl, optionally substituted heteroaryl, or optionally substituted arylalkyl;


A is oxygen or nitrogen;


d.sub.1 represents the distance between A and the geometric center of AR1 and is between 3 and 6 angstroms in at least one energetically accessible conformer of the compound;


d.sub.2 represents the distance between A and the geometric center of AR2 and is between 5 and 10 angstroms in at least one energetically accessible conformer of the compound; and


d.sub.3 represents the distance between A and the nearest atom of LIP and is between 3 and 6 angstroms in at least one energetically accessible conformer of the compound.


Preferred compounds of the invention also include heterocycles of the following formula II: ##STR3##


or a pharmaceutically acceptable salt thereof, wherein the compound exhibits an EC.sub.50 of 1 uM or less in an assay of C5a mediated chemotaxis, wherein:


the ring system represented by ##STR4##


 is a 5 to 7 membered heterocycle that may be either aromatic or partially unsaturated; X is N, C, or CR.sub.7, wherein R.sub.7 is hydrogen, hydroxy, halogen, amino, cyano, nitro, optionally substituted haloalkyl, optionally substituted alkoxy,
optionally substituted mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted (cycloalkyl)alkyl; Y is N or CH; n is 0, 1, or 2; m is 0, 1, or 2; R and R.sub.1 are
independently chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from
1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; R.sub.2, R.sub.3, R.sub.3A, R.sub.5, and R.sub.6 are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, optionally substituted haloalkyl, optionally
substituted alkoxy, optionally substituted mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl;


When n is 0, R.sub.1 and R.sub.3 may be joined to form a cycloalkyl or heterocycloalkyl ring, each of which may be optionally substituted;


When n is 1, R and R.sub.3 may be joined to form a cycloalkyl or heterocycloalkl ring, each of which may be optionally substituted;


R.sub.4 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally substituted; or


R.sub.4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and


Ar.sub.1 and Ar.sub.2 are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3
heteroatoms.


Preferred compounds of the above Formula II include those compounds wherein:


R and R.sub.1 are independendently selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may be unsubstituted
or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino, iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl,
oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl,
trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;


R.sub.2, R.sub.3, R.sub.3A, R.sub.5, and R.sub.6 are independently selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl,
each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino;


R.sub.7 is hydrogen, hydroxy, halogen, amino, cyano, nitro, or haloalkyl, or


R.sub.7 is alkoxy, mono- or dialkylamino, alkyl, alkenyl, alkynyl or (cycloalkyl)alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,
alkoxy, amino, and mono- or dialkylamino;


When n is 0, R.sub.1 and R.sub.3 may be joined to form a cycloalkyl or heterocycloalkyl ring, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino;


When n is 1, R and R.sub.3 may be joined to form a cycloalkyl or heterocycloalkyl ring, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;


R.sub.4 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,
acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; or


R.sub.4 is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl,
indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or
substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, carboxylic acid, esters of carboxylic
acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR5##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; and


Ar.sub.1 and Ar.sub.2 are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,
pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or
dialkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl, and ii) bicyclic oxygen-containing groups of the formula: ##STR6##
wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino.


Additional preferred compounds of the above formula II include those wherein


R and R.sub.1 are independently selected from i) hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, haloalkyl, and ii) C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, and (C.sub.3 -C.sub.8)cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,
acetoxy, alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino, iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of
which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


When n is 0, R.sub.1 and R.sub.3 may be joined to form a C.sub.3 -C.sub.8 cycloalkyl or C.sub.3 -C.sub.8 heterocycloalkyl ring, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino;


When n is 1, R and R.sub.3 may be joined to form a C.sub.3 -C.sub.8 cycloalkyl or C.sub.3 -C.sub.8 heterocycloalkyl ring, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.2, R.sub.3, R.sub.3A, R.sub.5, and R.sub.6 are independently selected from i) hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, haloalkyl, and ii) C.sub.1 -C.sub.8 alkyl,
C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, and (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl,
trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.7 is hydrogen, hydroxy, halogen, amino, cyano, nitro, or haloalkyl,


R.sub.7 is alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl or (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted by
one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted with one or more
substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1
-C.sub.6)alkylamino; or


R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl,
naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be
optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl,
C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl,
1-pyrrolidinyl, and 1-piperidyl; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR7##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino; and


Ar.sub.1 and Ar.sub.2 are independently chosen from phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl,
pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or
quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6
alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1 -C.sub.6)
alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl; and ii) bicyclic oxygen-containing groups of the formula: ##STR8## wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Still additional preferred compounds of the above formula II include those compounds of the following fomula: ##STR9##


and additionally include those compounds of the following formula: ##STR10##


m is 0, 1, or 2;


R.sub.1 is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl,
optionally substituted (cycloalkyl)alkyl, optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3
heteroatoms;


R.sub.2, R.sub.3, R.sub.3A, R.sub.5, and R.sub.6 are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl;


R.sub.4 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally substituted; or


R.sub.4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and


Ar.sub.1 and Ar.sub.2 are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3
heteroatoms.


Additional preferred compounds of the above formula II include those compounds of the following formula: ##STR11##


wherein:


R.sub.1 is hydrogen, C.sub.1 -C.sub.7 alkyl, halogen or phenyl optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, halogen, hydroxy, amino, or mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.2 is C.sub.1 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl; and


R.sub.3 is hydrogen or C.sub.1 -C.sub.7 alkyl.


Additional preferred compounds of the above formula II include those compounds of the following formula: ##STR12##


wherein:


Ar.sub.1 is phenyl, phenylalkyl, thienyl, imidazolyl, pyridyl, pyrimidyl, benzodioxinyl, benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.2 is defined as in claim 2;


R.sub.1 is hydrogen, C.sub.1 -C.sub.7 alkyl, halogen or phenyl optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, halogen, hydroxy, amino, or mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.2 is C.sub.1 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl; and


R.sub.3 is hydrogen or C.sub.1 -C.sub.7 alkyl; and


R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl, or (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Additional preferred compounds of the above formula II include those compounds of the following formula: ##STR13##


wherein:


Ar.sub.1 is phenyl, phenylalkyl, thienyl, imidazolyl, pyridyl, pyrimidyl, benzodioxinyl, benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.2 is defined as in claim 4;


R.sub.1 is hydrogen, C.sub.1 -C.sub.7 alkyl, halogen or phenyl optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, halogen, hydroxy, amino, or mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.2 is C.sub.1 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl; and


R.sub.3 is hydrogen or C.sub.1 -C.sub.7 alkyl; and


R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl,
naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be
optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl,
C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR14##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Additional preferred compounds of the above formula II include those compounds of the following formula: ##STR15##


wherein:


Ar.sub.1 is phenyl, phenylalkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,
acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.2 is defined as in formula II;


R.sub.1 is hydrogen, methyl, ethyl, or optionally substituted phenyl;


R.sub.2 is C.sub.3 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl; and


R.sub.3 is hydrogen or methyl; and


R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl, or (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Additional preferred compounds of the above formula II include those of the following formula: ##STR16##


wherein:


Ar.sub.1 is phenyl, phenylalkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,
acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.2 is defined as in claim 4;


R.sub.1 is hydrogen, methyl, ethyl, or phenyl;


R.sub.2 is C.sub.3 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl; and


R.sub.3 is hydrogen or methyl; and


R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,.  C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl,
C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR17##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Still additional preferred compounds of the above formula Ii include of the following formula: ##STR18##


wherein:


Ar.sub.1 is phenyl, phenylalkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,
acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.2 is chosen from phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, and
quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6
alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl; or


Ar.sub.2 is a bicyclic oxygen-containing groups of the formula: ##STR19##


 wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.1 is hydrogen, methyl, ethyl, or phenyl;


R.sub.2 is C.sub.3 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl; and


R.sub.3 is hydrogen or methyl; and


R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl, or (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Still further preferred compounds of the above formula II include those of the following formula: ##STR20##


wherein:


Ar.sub.1 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.2 is chosen from phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, and
quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6
alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl; or


Ar.sub.2 is a bicyclic oxygen-containing groups of the formula: ##STR21##


 wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.1 is hydrogen, methyl, ethyl, or phenyl;


R.sub.2 is C.sub.3 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl; and


R.sub.3 is hydrogen or methyl; and


R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR22##


wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Preferred compounds of the invention also include those of the following formula III: ##STR23##


or a pharmaceutically acceptable salt thereof, wherein:


Ar.sub.1 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
haloalkyl, hydroxy,


acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.2 is a bicyclic oxygen-containing groups of the formula: ##STR24##


 wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.1 is selected from i) hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, haloalkyl, and ii) C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3
-C.sub.8 cycloalkyl, and (C.sub.3 -C.sub.8)cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and
mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R.sub.1 is selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or
substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.2 and R.sub.3 are independently selected from i) hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, haloalkyl, and ii) C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, and (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,
acetoxy, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino; and


R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted with one or more
substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1
-C.sub.6)alkylamino; or


R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl,
naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be
optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl,
C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl,
1-pyrrolidinyl, and 1-piperidyl; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR25##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Preferred compounds of the above formula III include those wherein:


R.sub.1 is hydrogen, methyl, ethyl, or phenyl;


R.sub.2 is C.sub.3 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl;


R.sub.3 is hydrogen or methyl; and


R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted with one or more
substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1
-C.sub.6)alkylamino.


Additional preferred compounds of formula III include those wherein:


R.sub.1 is hydrogen, methyl, ethyl, or phenyl;


R.sub.2 is C.sub.3 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl;


R.sub.3 is hydrogen or methyl; and


R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted with one or more
substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1
-C.sub.6)alkylamino.


Still additional preferred compounds of formula III above include those wherein:


R.sub.1 is hydrogen, methyl, ethyl, or phenyl;


R.sub.2 is C.sub.3 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl;


R.sub.3 is hydrogen or methyl; and


phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of
which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino.


Preferred compounds of formula III above also include those wherein:


R.sub.1 is hydrogen, methyl, ethyl, or phenyl;


R.sub.2 is C.sub.3 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl;


R.sub.3 is hydrogen or methyl; and


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR26##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


The invention also includes compounds of the following formula IV: ##STR27##


or a pharmaceutically acceptable salt thereof, wherein:


n is an integer from 0 to 3; and


R.sub.2 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, or haloalkyl, each or which may be substituted or unsubstituted;


R.sub.4 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, each or which may be substituted or unsubstituted; or


R.sub.4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms,


R.sub.3 and R.sub.3A are the same or different and represent hydrogen or alkyl; or


R.sub.3 and R.sub.3A, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;


R.sub.5 and R.sub.6 are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or


R.sub.5 and R.sub.6, taken together with the carbon atom to which they are attached form a cycloalkyl ring;


R.sub.5a and R.sub.6a are the same or different, and are independently selected at each occurrence from hydrogen, halogen, hydroxy, alkyl, and alkoxy;


R.sub.7 represents hydrogen or alkyl;


Ar.sub.1 and Ar.sub.2 are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1
to 3 hetero atoms.


Also preferred are compounds of that formula IV above (such preferred compounds referred to as compounds of formula IV-A) wherein n, R.sub.3, R.sub.3A, R.sub.5, R.sub.6, R.sub.5a, R.sub.6a, and R.sub.7 are as defined in that formula IV, and


R.sub.2 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, or haloalkyl, each or which unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluormethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,
alkoxy, amino, and mono- or dialkylamino;


R.sub.4 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- or dialkylamino,


R.sub.4 is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl,
indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or
substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of
carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and --XR.sub.B, wherein X and R.sub.B are as defined below; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR28##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;


Ar.sub.1 and Ar.sub.2 are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,
pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or
dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and --XR.sub.B, wherein X and R.sub.B are as defined below;, and
ii) bicyclic oxygen-containing groups of the formula: ##STR29## wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and
mono- or dialkylamino;


X is independently selected at each occurrence from the group consisting of --CH.sub.2 --, --CHR.sub.C --, --O--, --S(O).sub.m --, --NH--, --NR.sub.C --, --C(.dbd.O)NH--, --C(.dbd.O)NR.sub.C --, --S(O).sub.m NH--, --S(O).sub.m NR.sub.C --,
--NHC(.dbd.O)--, --NR.sub.C C(.dbd.O)--, --NHS(O).sub.m --, --C(.dbd.O)NHS(O).sub.m --, and --NR.sub.C S(O).sub.m -- (where m is 0, 1, or 2); and


R.sub.B and R.sub.C, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each
of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, --O(alkyl), --NH(alkyl), --N(alkyl)(alkyl), --NHC(O)(alkyl), --N(alkyl)C(O)(alkyl), --NHS(O).sub.x (alkyl), --S(O).sub.x (alkyl), --S(O).sub.x
NH(alkyl), --S(O).sub.x N(alkyl)(alkyl), (where x is 0, 1, or 2).


Also preferred are compounds of formula IV above wherein (such preferred compounds referred to as compounds of formula IV-B)


n is defined as in formula IV above, and


R.sub.3 and R.sub.3A are the same or different and represent hydrogen or


C.sub.1 -C.sub.6 alkyl; or


R.sub.3 and R.sub.3A, taken together with the carbon atom to which they are attached, form a C.sub.3 -.sub.8 cycloalkyl ring;


R.sub.5 and R.sub.6 are the same or different and represent hydrogen, halogen, hydroxy, C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.6 alkoxy; or


R.sub.5 and R.sub.6, taken together with the carbon atom to which they are attached form a C.sub.3 -.sub.8 cycloalkyl ring;


R.sub.5a and R.sub.6b are the same or different, and are independently selected at each occurrence from hydrogen, halogen, hydroxy, C.sub.1 -C.sub.6 alkyl, and C.sub.1 -C.sub.6 alkoxy;


R.sub.2 is hydrogen or C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl) C.sub.1-3 alkyl, or C.sub.1 -C.sub.6 haloalkyl, each or which unsubstituted or substituted by one or more of halogen,
nitro, cyano, trifluormethyl, trifluoromethoxy, C.sub.1-3 haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.4 is hydrogen or C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-8 cycloalkyl, (C.sub.3 -.sub.8 cycloalkyl)C.sub.1-4 alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected
from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino and mono- or di(C.sub.1 -C.sub.6)alkylamino,


R.sub.4 is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl,
indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or
substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or
di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,
1-piperidyl, --XR.sub.B, wherein X and R.sub.B are as defined below; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR30##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2 -.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and
mono- or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.1 and Ar.sub.2 are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,
pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and --XR.sub.B, wherein X and R.sub.B are as defined below; and ii) bicyclic oxygen-containing groups of the formula: ##STR31## wherein R.sub.B represents 0 to 3 groups
selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


X is independently selected at each occurrence from the group consisting of --CH.sub.2 --, --CHR.sub.C --, --O--, --S(O).sub.m --, --NH--, --NR.sub.C --, --C(.dbd.O)NH--, --C(.dbd.O)NR.sub.C --, --S(O).sub.m NH--, --S(O).sub.m NR.sub.C --,
--NHC(.dbd.O)--, --NR.sub.C C(.dbd.O)--, --NHS(O).sub.m --, --C(.dbd.O)NHS(O).sub.m --, and --NR.sub.C S(O).sub.m -- (where m is 0, 1, or 2); and


R.sub.B and R.sub.C, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each
of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, --O(C.sub.1 -C.sub.6 alkyl), --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), --NHC(O)(C.sub.1 -C.sub.6 alkyl),
--N(C.sub.1 -C.sub.6 alkyl)C(O)(C.sub.1-6 alkyl), --NHS(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x NH(C.sub.1 -C.sub.6 alkyl), --S(O).sub.x N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), (where x is 0, 1,
or 2).


Also preferred are compounds of formula IV above (such preferred referred to as compounds of formula IV-C) wherein n, R.sub.2, R.sub.3, R.sub.3A, R.sub.5, R.sub.6, R.sub.5a, R.sub.6a, and R.sub.7 are as defined in formula IV above,


R.sub.4 is hydrogen or


C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.4 alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more
substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino and mono- or di(C.sub.1
-C.sub.6)alkylamino,


R.sub.4 is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic
acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, --XR.sub.B, wherein X and R.sub.B are as defined below; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR32##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.1 is phenyl, thienyl, or pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which is unsubstituted or substituted with up to four substituents independently selected from: halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic
acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and --XR.sub.B, wherein X and R.sub.B are as defined below;


Ar.sub.2 is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic
acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and --XR.sub.B, wherein X and R.sub.B are as defined below; or


Ar.sub.2 is a bicyclic oxygen-containing group of the formula: ##STR33##


 wherein R.sub.A ' represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


X is independently selected at each occurrence from the group consisting of --CH.sub.2 --, --CHR.sub.C --, --O--, --S(O).sub.m --, --NH--, --NR.sub.C --, --C(.dbd.O)NH--, --C(.dbd.O)NR.sub.C --, --S(O).sub.m NH--, --S(O).sub.m NR.sub.C --,
--NHC(.dbd.O)--, --NR.sub.C C(.dbd.O)--, --NHS(O).sub.m --, --C(.dbd.O)NHS(O).sub.m --, and --NR.sub.C S(O).sub.m -- (where m is 0, 1, or 2); and


R.sub.B and R.sub.C, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each
of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, --O(C.sub.1 -C.sub.6 alkyl), --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), --NHC(O)(C.sub.1 -C.sub.6 alkyl),
--N(C.sub.1 -C.sub.6 alkyl)C(O)(C.sub.1 -C.sub.6 alkyl), --NHS(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x NH(C.sub.1 -C.sub.6 alkyl), --S(O).sub.x N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), (where x is
0, 1, or 2).


Further preferred are compounds of the above formula IV-C wherein:


R.sub.3 and R.sub.4 are the same or different and represent hydrogen or methyl;


R.sub.5 and R.sub.6 are the same or different and represent hydrogen or methyl; and


R.sub.5a and R.sub.6a are the same or different, and are independently selected at each occurrence from hydrogen and methyl.


Further preferred are compounds of the above formula IV-C wherein:


R.sub.3 and R.sub.4 are hydrogen;


R.sub.5 and R.sub.6 are the same or different and represent hydrogen or methyl; and


R.sub.5a and R.sub.6a are the same or different, and are independently selected at each occurrence from hydrogen and methyl.


Further preferred are compounds of the above formula IV-C wherein: ##STR34##


or a pharmaceutically acceptable salt thereof, wherein:


n is an integer from 0 to 3; and


R.sub.2 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, or haloalkyl, each or which may be substituted or unsubstituted;


R.sub.4 is hydrogen or C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.4 alkyl, haloalkyl, each or which may be unsubstituted or substituted
with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino and mono- or
di(C.sub.1 -C.sub.6)alkylamino,


R.sub.4 is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic
acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, --XR.sub.B, wherein X and R.sub.B are as defined below; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR35##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.2 is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic
acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and --XR.sub.B, wherein X and R.sub.B are as defined below; or


Ar.sub.2 is a bicyclic oxygen-containing group of the formula: ##STR36##


 wherein R.sub.A ' represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


X is independently selected at each occurrence from the group consisting of --CH.sub.2 --, --CHR.sub.C --, --O--, --S(O).sub.m --, --NH--, --NR.sub.C --, --C(.dbd.O)NH--, --C(.dbd.O)NR.sub.C --, --S(O).sub.m NH--, --S(O).sub.m NR.sub.C --,
--NHC(.dbd.O)--, --NR.sub.C C(.dbd.O)--, --NHS(O).sub.m --, --C(.dbd.O)NHS(O).sub.m --, and --NR.sub.C S(O).sub.m -- (where m is 0, 1, or 2); and


R.sub.B and R.sub.C, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each
of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, --O(C.sub.1 -C.sub.6 alkyl), --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), --NHC(O)(C.sub.1 -C.sub.6 alkyl),
--N(C.sub.1 -C.sub.6 alkyl)C(O)(C.sub.1 -C.sub.6 alkyl), --NHS(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x NH(C.sub.1 -C.sub.6 alkyl), --S(O).sub.x N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), (where x is
0, 1, or 2).


R.sub.5 and R.sub.6 are the same or different and represent hydrogen or methyl;


R.sub.5a and R.sub.6a are the same or different, and are independently chosen at each occurrence from hydrogen and methyl; and


R.sub.x represents up to four substituents independently chosen from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl,
C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, and amino(C.sub.1 -C.sub.6)alkoxy.


Further preferred are compounds of the above formula IV-C wherein: ##STR37##


or a pharmaceutically acceptable salt thereof, wherein:


n is an integer from 0 to 3; and


R.sub.4 is hydrogen or C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.4 alkyl, haloalkyl, each or which may be unsubstituted or substituted
with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino and mono- or
di(C.sub.1 -C.sub.6)alkylamino,


R.sub.4 is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic
acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, --XR.sub.B, wherein X and R.sub.B are as defined below; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR38##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.2 is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic
acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and --XR.sub.B, wherein X and R.sub.B are as defined below; or


Ar.sub.2 is a bicyclic oxygen-containing group of the formula: ##STR39##


 wherein R.sub.A ' represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


X is independently selected at each occurrence from the group consisting of --CH.sub.2 --, --CHR.sub.C --, --O--, --S(O).sub.m --, --NH--, --NR.sub.C --, --C(.dbd.O)NH--, --C(.dbd.O)NR.sub.C --, --S(O).sub.m NH--, --S(O).sub.m NR.sub.C --,
--NHC(.dbd.O)--, --NR.sub.C C(.dbd.O)--, --NHS(O).sub.m --, --C(.dbd.O)NHS(O).sub.m --, and --NR.sub.C S(O).sub.m -- (where m is 0, 1, or 2); and


R.sub.B and R.sub.C, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each
of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, --O(C.sub.1 -C.sub.6 alkyl), --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), --NHC(O)(C.sub.1 -C.sub.6 alkyl),
--N(C.sub.1 -C.sub.6 alkyl)C(O)(C.sub.1 -C.sub.6 alkyl), --NHS(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x NH(C.sub.1 -C.sub.6 alkyl), --S(O).sub.x N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), (where x is
0, 1, or 2).


R.sub.2 is C.sub.3 -C.sub.8 straight or branched chain alkyl, C.sub.2 -C.sub.8 alkenyl, or C.sub.2 -C.sub.8 alkynyl;


R.sub.5 and R.sub.6 are the same or different and represent hydrogen or methyl;


R.sub.5a and R.sub.6a are the same or different, and are independently chosen at each occurrence from hydrogen and methyl; and


R.sub.x represents up to four substituents independently chosen from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl,
C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, and amino(C.sub.1 -C.sub.6)alkoxy.


Further preferred are compounds of the above formula IV-C wherein:


Ar.sub.2, R.sub.x, and n are as defined in formula IV-C, or a pharmaceutically acceptable salt thereof, wherein: R.sub.2 is C.sub.3 -C.sub.8 straight or branched chain alkyl, C.sub.2 -C.sub.8 alkenyl, or C.sub.2 -C.sub.8 alkynyl; and


R.sub.4 is C.sub.1 -C.sub.8 straight or branched chain alkyl, C.sub.2 -C.sub.8 alkenyl, or C.sub.2 -C.sub.8 alkynyl.


Further preferred are compounds of the above formula IV-C, or a pharmaceutically acceptable salt thereof, wherein:


R.sub.2 is C.sub.3 -C.sub.8 straight or branched chain alkyl, C.sub.2 -C.sub.8 alkenyl, or C.sub.2 -C.sub.8 alkynyl;


R.sub.4 is phenyl, which may be unsubstituted or substituted with: C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl)C.sub.1 -C.sub.4 alkyl, haloalkyl, C.sub.1
-C.sub.6 alkoxy, halogen, hydroxy, amino, or mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R.sub.4 is a bicyclic oxygen containing group of the formula: ##STR40##


 wherein R.sub.A is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.4 alkyl, haloalkyl, alkoxy, halogen, hydroxy, amino, or mono- or
di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.2 is phenyl which is unsubstituted or optionally substituted or substituted with up to four groups independently selected from: halogen, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, cyano, amino, mono- or di(C.sub.1
-C.sub.6)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, 1-morpholino, nitro, hydroxy, acetoxy, trifluoromethyl, and
trifluoromethoxy or --XR.sub.B, wherein X and R.sub.B are as defined for formula IV-C; or


Ar.sub.2 is a bicyclic oxygen-containing group of the formula: ##STR41##


 wherein R.sub.A R.sub.A ', and n are as defined in formula IV-C.


Also preferred are compounds of formula IV-C as specified above, wherein:


n is an integer from 0 to 3;


R.sub.2 is C.sub.3 -C.sub.8 straight or branched chain alkyl, C.sub.2 -C.sub.8 alkenyl, or C.sub.2 -C.sub.8 alkynyl;


R.sub.4 is C.sub.1 -C.sub.8 straight or branched chain alkyl, C.sub.2 -C.sub.8 alkenyl, or C.sub.2 -C.sub.8 alkynyl;


Ar.sub.2 is a bicyclic oxygen containing group of the formula: ##STR42##


 wherein R.sub.A ' represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Additional preferred compounds include those of the following formula V: ##STR43##


wherein:


n is an integer from 0 to 3;


R.sub.3 and R.sub.3A are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or


R.sub.3 and R.sub.3A, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;


R.sub.5 and R.sub.6 are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or


R.sub.5 and R.sub.6, taken together with the carbon atom to which they are attached form a cycloalkyl ring; and


R.sub.5A and R.sub.6A are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy.


Preferred compounds of formula V include those compounds wherein:


R.sub.3 and R.sub.3A are the same or different and represent hydrogen or C.sub.1 -C.sub.6 alkyl; or


R.sub.3 and R.sub.3A, taken together with the carbon atom to which they are attached, form a cycloalkyl ring of from three to six carbon atoms;


R.sub.5 and R.sub.6 are the same or different and represent hydrogen, halogen, hydroxy, C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.6 alkoxy; or


R.sub.5 and R.sub.6, taken together with the carbon atom to which they are attached form a cycloalkyl ring of from three to six carbon atoms; and


R.sub.5A and R.sub.6A are the same or different and represent hydrogen, halogen, hydroxy, C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.6 alkoxy.


Preferred compounds of formula V include thosae compounds wherein:


R.sub.3 and R.sub.4 are hydrogen; and


R.sub.5, R.sub.6, R.sub.5A, and R.sub.6A are the same or different and represent hydrogen or methyl.


The invention also includes compounds of the following formula VI: ##STR44##


wherein:


n is an integer from 0 to 3;


R.sub.2 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, or haloalkyl, each of which may be substituted or unsubstituted;


R.sub.3 and R.sub.4 are the same or different and represent hydrogen or alkyl; or


R.sub.3 and R.sub.3a, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;


R.sub.5 and R.sub.6 are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or


R.sub.5 and R.sub.6, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;


R.sub.5 A and R.sub.6 A are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; and


Ar.sub.1 is unsubstituted or substituted carbocyclic aryl, unsubstituted or substituted arylalkyl, or a unsubstituted or substituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3
hetero atoms.


Preferred compounds of formula VI include those compounds wherein:


R.sub.2 is C.sub.1 -C.sub.8 straight or branched chain alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.2 -C.sub.8 (cycloalkyl)C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.8 haloalkyl;


R.sub.3 and R.sub.3a are the same or different and represent hydrogen or C.sub.1 -C.sub.6 alkyl; or


R.sub.3 and R.sub.3a, taken together with the carbon atom to which they are attached, form a cycloalkyl ring of from three to six carbon atoms; and


R.sub.5 and R.sub.6 are the same or different and represent hydrogen, halogen, hydroxy, C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.6 alkoxy; or


R.sub.5 and R.sub.6, taken together with the carbon atom to which they are attached form a cycloalkyl ring of from three to six carbon atoms;


R.sub.5A and R.sub.6A are the same or different and represent hydrogen, halogen, hydroxy, C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.6 alkoxy;


Ar.sub.1 is phenyl, thienyl, or pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which is unsubstituted or substituted with up to four substituents independently selected from: halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic
acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N-(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and --XR.sub.B, wherein X and R.sub.B are as defined below;


X is independently selected at each occurrence from the group consisting of --CH.sub.2 --, --CHR.sub.C --, --O--, --S(O).sub.m --, --NH--, --NR.sub.C --, --C(.dbd.O)NH--, --C(.dbd.O)NR.sub.C --, --S(O).sub.m NH--, --S(O).sub.m NR.sub.C --,
--NHC(.dbd.O)--, --NR.sub.C C(.dbd.O)--, --NHS(O).sub.m --, --C(.dbd.O)NHS(O).sub.m --, and --NR.sub.C S(O).sub.m -- (where m is 0, 1, or 2); and


R.sub.B and R.sub.C, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each
of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, --O(C.sub.1 -C.sub.6 alkyl), --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), --NHC(O)(C.sub.1 -C.sub.6 alkyl),
--N(C.sub.1 -C.sub.6 alkyl)C(O)(C.sub.1 -C.sub.6 alkyl), --NHS(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x NH(C.sub.1 -C.sub.6 alkyl), --S(O).sub.x N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), (where x is
0, 1, or 2).


Preferred compounds of the above formula VI include those of the following formula: ##STR45##


wherein:


n is 0, 1, or 2:


R.sub.2 is C.sub.3 -C.sub.8 straight or branched chain alkyl, C.sub.2 -C.sub.8 alkenyl, or C.sub.2 -C.sub.8 alkynyl;


R.sub.5, R.sub.6, R.sub.5A, and R.sub.6A are the same or different and represent hydrogen or methyl; and


R.sub.X represents up to four substituents independently chosen from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl,
C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, and amino(C.sub.1 -C.sub.6)alkoxy.


The invention also includes compounds of the following formula VII: ##STR46##


wherein:


n is an integer from 0 to 3; and


R.sub.2 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, each or which may be substituted or unsubstituted;


R.sub.3 and R.sub.3A are the same or different and represent hydrogen or alkyl; or


R.sub.3 and R.sub.3a, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;


R.sub.5 and R.sub.6 are the same or different and represent hydrogen or alkyl; or.


R.sub.5 and R.sub.6, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;


R.sub.5a and R.sub.6a are the same or different, and are independently selected at each occurrence from hydrogen, halogen, hydroxy, alkyl, and alkoxy;


R.sub.7 represents hydrogen or alkyl; and


Ar.sub.1 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms.


Preferred compounds of formula VII include those of the following formula: ##STR47##


wherein:


n is an integer from 0 to 3;


R.sub.2 is C.sub.3 -C.sub.8 straight or branched chain alkyl, C.sub.2 -C.sub.8 alkenyl, or C.sub.2 -C.sub.8 alkynyl;


R.sub.5, R.sub.6, R.sub.5A, and R.sub.6A are the same or different and represent hydrogen or methyl; and


R.sub.X represents up to four substituents independently chosen from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl,
C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, and amino(C.sub.1 -C.sub.6)alkoxy.


The invention also includes methods of syntesis of compounds of the invention.  In particular, the invention includes methods to synthesis compounds of the following formula VIII: ##STR48##


wherein:


n is an integer from 0 to 3; and


R.sub.2 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, or haloalkyl, each or which may be substituted or unsubstituted;


R.sub.4 is hydrogen or alkyl alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, each or which may be substituted or unsubstituted; or


R.sub.4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms,


R.sub.3 and R.sub.3A are the same or different and represent hydrogen or alkyl; or


R.sub.3 and R.sub.3A, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;


R.sub.5 and R.sub.6 are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or


R.sub.5 and R.sub.6, taken together with the carbon atom to which they are attached form a cycloalkyl ring;


R.sub.5a and R.sub.6a are the same or different, and are independently selected at each occurrence from hydrogen, halogen, hydroxy, alkyl, and alkoxy;


R.sub.7 represents hydrogen or alkyl;


Ar.sub.1 and Ar.sub.2 are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1
to 3 hetero atoms.


The process comprising:


reacting a compound of the formula: ##STR49##


 wherein Y is halogen or sulfonate ester, in a suitable solvent in the presence of a suitable base, with a secondary amine of the formula: ##STR50##


In that synthetic method, preferred are compounds (referred to as compounds of formula VIII-A) wherein


n and Y are as defined above for formula VIII;


R.sub.3 and R.sub.3A are the same or different and represent hydrogen or C.sub.1 -C.sub.6 alkyl; or


R.sub.3 and R.sub.3A, taken together with the carbon atom to which they are attached, form a C.sub.3-8 cycloalkyl ring;


R.sub.5 and R.sub.6 are the same or different and represent hydrogen, halogen, hydroxy, C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.6 alkoxy; or


R.sub.5 and R.sub.6, taken together with the carbon atom to which they are attached form a C.sub.3-8 cycloalkyl ring;


R.sub.5a and R.sub.6a are the same or different, and are independently selected at each occurrence from hydrogen, halogen, hydroxy, C.sub.1 -C.sub.6 alkyl, and C.sub.1 -C.sub.6 alkoxy;


R.sub.2 is hydrogen or


C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl) C.sub.1-3 alkyl, or C.sub.1 -C.sub.6 haloalkyl, each or which unsubstituted or substituted by one or more of halogen, nitro, cyano,
trifluormethyl, trifluoromethoxy, C.sub.1-3 haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.4 is hydrogen or C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl) C.sub.1-4 alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from
halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino and mono- or di(C.sub.1 -C.sub.6)alkylamino,


R.sub.4 is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl,
indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or
substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or
di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,
1-piperidyl, --XR.sub.B, wherein X and R.sub.B are as defined below; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR51##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono-
or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.1 and Ar.sub.2 are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,
pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and --XR.sub.B, wherein X and R.sub.B are as defined below; and ii) bicyclic oxygen-containing groups of the formula: ##STR52## wherein R.sub.B represents 0 to 3 groups
selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


X is independently selected at each occurrence from the group consisting of --CH.sub.2 --, --CHR.sub.C --, --O--, --S(O).sub.m --, --NH--, --NR.sub.C --, --C(.dbd.O)NH--, --C(.dbd.O)NR.sub.C --, --S(O).sub.m NH--, S(O).sub.m NR.sub.C --,
--NHC(.dbd.O)--, --NR.sub.C C(.dbd.O)--, --NHS(O).sub.m --, --C(.dbd.O)NHS(O).sub.m --, and --NR.sub.C S(O).sub.m -- (where m is 0, 1, or 2); and


R.sub.B and R.sub.C, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each
of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, --O(C.sub.1 -C.sub.6 alkyl), --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), --NHC(O)(C.sub.1 -C.sub.6 alkyl),
--N(C.sub.1 -C.sub.6 alkyl)C(O)(C.sub.1 -C.sub.6 alkyl), --NHS(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x NH(C.sub.1 -C.sub.6 alkyl), --S(O).sub.x N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), (where x is
0, 1, or 2).


The invention also includes compounds of the above formula VIII and VIII-A, and pharmaceutically acceptable salts of such compounds.


The invention also provides compounds of the following formula IX: ##STR53##


or a pharmaceutically acceptable salt thereof, wherein:


m is 0, 1, or 2;


R is hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally
substituted (cycloalkyl)alkyl; or


R is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;


R.sub.1, R.sub.2, R.sub.3, R.sub.3A, R.sub.5, and R.sub.6 are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl;


R.sub.4 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally substituted; or


R.sub.4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and


Ar.sub.1 and Ar.sub.2 are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3
heteroatoms.


Preferred compounds of formula IX include those of the following formula IX-A: ##STR54##


wherein Ar.sub.1, Ar.sub.2, R, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are for formula IX above.


Preferred compounds of formula IX-A above include those wherein:


R is selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may be unsubstituted or substituted by one or more
of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino; or


R is selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or
substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; and


R.sub.1, R.sub.2, and R.sub.3 are independently selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may be
unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino;


R.sub.4 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- or dialkylamino,


R.sub.4 is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl., pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl,
indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or
substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of
carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, --XR.sub.B, wherein X and R.sub.B are as defined below; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR55##


wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;


Ar.sub.1 and Ar.sub.2 are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,
pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or
dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and --XR.sub.B, wherein X and R.sub.B are as defined below; and
ii) bicyclic oxygen-containing groups of the formula: ##STR56## wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and
mono- or dialkylamino;


X is independently selected at each occurrence from the group consisting of --CH.sub.2 --, --CHR.sub.C --, --O--, --S(O).sub.m --, --NH--, --NR.sub.C --, --C(.dbd.O)NH--, --C(.dbd.O)NR.sub.C --, --S(O).sub.m NH--, --S(O).sub.m NR.sub.C --,
--NHC(.dbd.O)--, --NR.sub.C C(.dbd.O)--, --NHS(O).sub.m --, --C(.dbd.O)NHS(O).sub.m --, and --NR.sub.C S(O).sub.m -- (where m is 0, 1, or 2); and


R.sub.B and R.sub.C, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each
of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, --O(alkyl), --NH(alkyl), --N(alkyl)(alkyl), --NHC(O)(alkyl), --N(alkyl)C(O)(alkyl), --NHS(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x (alkyl),
--S(O).sub.x NH(alkyl), --S(O).sub.x N(alkyl)(alkyl), (where x is 0, 1, or 2).


Additional preferred compounds of formula IX-A include those wherein:


R.sub.1, R.sub.2, and R.sub.3 are independently selected from i) hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, haloalkyl, and ii) C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6
alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, and (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino;


R is selected from i) hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, haloalkyl, and ii) C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3
-C.sub.8 cycloalkyl, and (C.sub.3-C.sub.8)cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and
mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R is selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or
substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.4 is hydrogen or C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl)C.sub.1-4 alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from
halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino and mono- or di(C.sub.1 -C.sub.6)alkylamino,


R.sub.4 is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl,
indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or
substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or
di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,
1-piperidyl, --XR.sub.B, wherein X and R.sub.B are as defined below; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR57##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono-
or di(C.sub.1 -C.sub.6)alkylamino; and


Ar.sub.1 and Ar.sub.2 are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,
pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benz[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and --XR.sub.B, wherein X and R.sub.B are as defined below; and ii) bicyclic oxygen-containing groups of the formula: ##STR58## wherein R.sub.B represents 0 to 3 groups
selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


X is independently selected at each occurrence from the group consisting of --CH.sub.2 --, --CHR.sub.C --, --O--, --S(O).sub.m --, --NH--, --NR.sub.C --, --C(.dbd.O)NH--, --C(.dbd.O)NR.sub.C --, --S(O).sub.m NH--, --S(O).sub.m NR.sub.C --,
--NHC(.dbd.O)--, --NR.sub.C C(.dbd.O)--, --NHS(O).sub.m --, --C(.dbd.O)NHS(O).sub.m --, and --NR.sub.C S(O).sub.m -- (where m is 0, 1, or 2); and


R.sub.B and R.sub.C, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each
of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, --O(C.sub.1 -C.sub.6 alkyl), --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), --NHC(O)(C.sub.1 -C.sub.6 alkyl),
--N(C.sub.1 -C.sub.6 alkyl)C(O)(C.sub.1 -C.sub.6 alkyl), --NHS(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x NH(C.sub.1 -C.sub.6 alkyl), --S(O).sub.x N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), (where x is
0, 1, or 2).


Additional preferred compounds of formula IX-A above include those wherein:


R is hydrogen, halogen, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.1 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl)C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.8 alkoxy, or C.sub.1 -C.sub.8 haloalkyl, or


R is a phenyl which may be substituted by up to five substituents independently chosen from C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.1 -C.sub.8 alkoxy, halogen, cyano, carboxylic acid, hydroxy, acetoxy,
nitro, amino, mono or di(C.sub.1 -C.sub.6)alkylamino, aminocarbonyl, sulfonamido, mono or di(C.sub.1 -C.sub.6)alkylsulfonamido, 3,4-methylenedioxy, 3,4-(1,2-ethylene)dioxy, trifluoromethyl or trifluoromethoxy;


R.sub.1 is hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl (C.sub.3 -C.sub.8 cycloalkyl)C.sub.1 -C.sub.3 alkyl or C.sub.1 -C.sub.8 haloalkyl;


R.sub.2 is C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.1 -C.sub.8 cycloalkyl or (C.sub.3 -C.sub.8 cycloalkyl)C.sub.1 -C.sub.3 alkyl or C.sub.1 -C.sub.8 haloalkyl;


R.sub.3 is hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, or C.sub.2 -C.sub.8 alkynyl;


R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl, or (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR59##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino; and


Ar.sub.1 and Ar.sub.2 are independently chosen from phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl,
quinolinyl, isoquinolinyl, and quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1
-C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl,
N--(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl, and bicyclic oxygen-containing groups of the formula: ##STR60##


 wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Still additional preferred compounds of formula IX-A include those compounds


wherein:


R is hydrogen, halogen, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.1 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl)C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.8 alkoxy, or C.sub.1 -C.sub.8 haloalkyl, or


R is a phenyl which may be substituted by up to five substituents independently chosen from C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.1 -C.sub.8 alkoxy, halogen, cyano, carboxylic acid, hydroxy, acetoxy,
nitro, amino, mono or di(C.sub.1 -C.sub.6)alkylamino, aminocarbonyl, sulfonamido, mono or di(C.sub.1 -C.sub.6)alkylsulfonamido, 3,4-methylenedioxy, 3,4-(1,2-ethylene)dioxy, trifluoromethyl or trifluoromethoxy;


R.sub.1 is hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl (C.sub.3 -C.sub.8 cycloalkyl)C.sub.1 -C.sub.3 alkyl or C.sub.1 -C.sub.8 haloalkyl;


R.sub.2 is C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.1 -C.sub.8 cycloalkyl or (C.sub.3 -C.sub.8 cycloalkyl)C.sub.1 -C.sub.3 alkyl or C.sub.1 -C.sub.8 haloalkyl;


R.sub.3 is hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, or C.sub.2 -C.sub.8 alkynyl;


R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl, or (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR61##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.1 is phenyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1
-C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino; and


Ar.sub.2 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, and
quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6
alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl, or


Ar.sub.2 is a bicyclic oxygen-containing group of the formula: ##STR62##


 wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Still further preferred compounds of formula IX above include those wherein


R is hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, or phenyl;


R.sub.1 is hydrogen, methyl or ethyl;


R.sub.2 is C.sub.3 -C.sub.6 alkyl;


R.sub.3 is hydrogen, methyl or ethyl;


R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl, or (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR63##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.1 is phenyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1
-C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino; and


Ar.sub.2 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, and
quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6
alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.2 is a bicyclic oxygen-containing group of the formula: ##STR64##


 wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


The invention also include compounds of the following formula X: ##STR65##


 wherein


m is 0, 1, or 2;


R is hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally
substituted (cycloalkyl)alkyl; or


R is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;


R.sub.1, R.sub.2, R.sub.3, R.sub.3A, R.sub.5, and R.sub.6 are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl;


R.sub.4 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally substituted; or


R.sub.4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and


Ar.sub.1 and Ar.sub.2 are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3
heteroatoms.


Preferred compounds of formula X include those of the following formula X-A: ##STR66##


wherein Ar.sub.1, R, R.sub.1, R.sub.2, R.sub.3, R.sub.4 are as defined for formula X above.


Additional preferred compounds of formula X include those wherein:


R.sub.1, R.sub.2, and R.sub.3 are independently selected from i) hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, haloalkyl, and ii) C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6
alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, and (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino;


R is selected from i) hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, haloalkyl, and ii) C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3
-C.sub.8 cycloalkyl, and (C.sub.3 -C.sub.8)cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and
mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R is selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or
substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.4 is hydrogen or C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl)C.sub.1-4 alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from
halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino and mono- or di(C.sub.1 -C.sub.6)alkylamino,


R.sub.4 is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl,
indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or
substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or
di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,
1-piperidyl, --XR.sub.B, wherein X and R.sub.B are as defined below; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR67##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono-
or di(C.sub.1 -C.sub.6)alkylamino; and


Ar.sub.1 and Ar.sub.2 are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,
pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and --XR.sub.B, wherein X and R.sub.B are as defined below; and ii) bicyclic oxygen-containing groups of the formula: ##STR68## wherein R.sub.B represents 0 to 3 groups
selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


X is independently selected at each occurrence from the group consisting of --CH.sub.2 --, --CHR.sub.C --, --O--, --S(O).sub.m --, --NH--, --NR.sub.C --, --C(.dbd.O)NH--, --C(.dbd.O)NR.sub.C --, --S(O).sub.m NH--, --S(O).sub.m NR.sub.C --,
--NHC(.dbd.O)--, --NR.sub.C C(.dbd.O)--, --NHS(O).sub.m --, --C(.dbd.O)NHS(O).sub.m --, and --NR.sub.C S(O).sub.m -- (where m is 0, 1, or 2); and


R.sub.B and R.sub.C, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each
of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, --O(C.sub.1 -C.sub.6 alkyl), --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), --NHC(O)(C.sub.1 -C.sub.6 alkyl),
--N(C.sub.1 -C.sub.6 alkyl)C(O)(C.sub.1 -C.sub.6 alkyl), --NHS(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x NH(C.sub.1 -C.sub.6 alkyl), --S(O).sub.x N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), (where x is
0, 1, or 2).


Additional preferred compounds of formula X above include those wherein:


R is hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, or phenyl;


R.sub.1 is hydrogen, methyl or ethyl;


R.sub.2 is C.sub.3 -C.sub.6 alkyl;


R.sub.3 is hydrogen, methyl or ethyl;


R.sub.4 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl, or (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR69##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino; and


Ar.sub.1 is phenyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1
-C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino.


The invention also includes compounds of the following formula XI: ##STR70##


or pharmaceutically acceptable salt thereof, wherein:


n is 0, 1, or 2;


R is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl,
optionally substituted (cycloalkyl)alkyl, optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3
heteroatoms;


R.sub.2, R.sub.3, R.sub.3A, R.sub.5, and R.sub.6 are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl;


R and R.sub.3 may be joined to form an optionally substituted saturated carbocylic ring of from 5 to 8 members or an optionally substituted heterocyclic ring of from 5 to 8 members;


R.sub.4 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally substituted; or


R.sub.4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and


Ar.sub.1 and Ar.sub.2 are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3
heteroatoms.


The invention further includes compounds of the following formula XII: ##STR71##


or a pharmaceutically acceptable salt thereof, wherein:


R is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl,
optionally substituted (cycloalkyl)alkyl, optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3
heteroatoms;


R.sub.2 and R.sub.3 are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl;


R and R.sub.3 may be joined to form an optionally substituted carbocylic ring of from 5 to 8 members or an optionally substituted heterocyclic ring of from 5 to 8 members;


R.sub.4 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally substituted; or


R.sub.4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and


Ar.sub.1 and Ar.sub.2 are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3
heteroatoms.


Preferred compounds of formula XII above include wherein R and R.sub.3 are not joined.


Also preferred are compounds of formula XII wherein: R is selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of
which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino, iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl,
thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl,
trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;


R.sub.2 and R.sub.3 are independently selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may be
unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino;


R.sub.4 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- or dialkylamino,


R.sub.4 is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl,
indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or
substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of
carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and --XR.sub.B, wherein X and R.sub.B are as defined below; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR72##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;


Ar.sub.1 and Ar.sub.2 are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,
pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or
dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and --XR.sub.B, wherein X and R.sub.B are as defined below;, and
ii) bicyclic oxygen-containing groups of the formula: ##STR73## wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and
mono- or dialkylamino;


X is independently selected at each occurrence from the group consisting of --CH.sub.2 --, --CHR.sub.C --, --O--, --S(O).sub.m --, --NH--, --NR.sub.C --, --C(.dbd.O)NH--, --C(.dbd.O)NR.sub.C --, S(O).sub.m NH--, --S(O).sub.m NR.sub.C --,
--NHC(.dbd.O)--, --NR.sub.C C(.dbd.O)--, --NHS(O).sub.m --, --C(.dbd.O)NHS(O).sub.m --, and --NR.sub.C S(O).sub.m -- (where m is 0, 1, or 2); and


R.sub.B and R.sub.C, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each
of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, --O(alkyl), --NH(alkyl), --N(alkyl)(alkyl), --NH C(O)(alkyl), --N(alkyl)C(O)(alkyl), --NHS(O).sub.x (alkyl), --S(O).sub.x (alkyl), --S(O).sub.x
NH(alkyl), --S(O).sub.x N(alkyl)(alkyl), (where x is 0, 1, or 2).


Additional preferred compounds of formula XII include those wherein:


R is selected from i) hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, haloalkyl, and ii) C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3
-C.sub.8 cycloalkyl, and (C.sub.3 -C.sub.8)cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and
mono- or di(C.sub.1 -C.sub.6)alkylamino, iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally
substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1
-C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.2 and R.sub.3 are independently selected from i) hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, haloalkyl, and ii) C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, and (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy,
acetoxy, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.4 is hydrogen or C.sub.1 -C.sub.8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl)C.sub.1-4 alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected
from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino and mono- or di(C.sub.1 -C.sub.6)alkylamino,


R.sub.4 is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl,
indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or
substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or
di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl,
1-piperidyl, --XR.sub.B, wherein X and R.sub.B are as defined below; or


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR74##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono-
or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.1 and Ar.sub.2 are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,
pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl,
each of which may be optionally substituted or substituted with up to four groups independently selected from.  halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and --XR.sub.B, wherein X and R.sub.B are as defined below; and ii) bicyclic oxygen-containing groups of the formula: ##STR75## wherein R.sub.B represents 0 to 3 groups
selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino;


X is independently selected at each occurrence from the group consisting of --CH.sub.2 --, --CHR.sub.C --, --O--, --S(O).sub.m --, --NH--, --NR.sub.C --, --C(.dbd.O)NH--, --C(.dbd.O)NR.sub.C --, --S(O).sub.m NH--, --S(O).sub.m NR.sub.C --,
--NHC(.dbd.O)--, --NR.sub.C C(.dbd.O)--, --NHS(O).sub.m --, --C(.dbd.O)NHS(O).sub.m --, and --NR.sub.C S(O).sub.m -- (where m is 0, 1, or 2); and


R.sub.B and R.sub.C, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each
of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, --O(C.sub.1 -C.sub.6 alkyl), --NH(C.sub.1 -C.sub.6 alkyl), --N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), --NHC(O)(C.sub.1 -C.sub.6 alkyl),
--N(C.sub.1 -C.sub.6 alkyl)C(O)(C.sub.1 -C.sub.6 alkyl), --NHS(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x (C.sub.1 -C.sub.6 alkyl), --S(O).sub.x NH(C.sub.1 -C.sub.6 alkyl), --S(O).sub.x N(C.sub.1 -C.sub.6 alkyl)(C.sub.1 -C.sub.6 alkyl), (where x is
0, 1, or 2).


Also preferred are compounds of formula XII wherein:


R is hydrogen, halogen, hydroxy, C.sub.1 -C.sub.6 alkoxy, haloalkyl, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, and (C.sub.3 -C.sub.8)cycloalkyl) C.sub.1 -C.sub.3 alkyl, or


R is phenyl substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1
-C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino, aminocarbonyl, sufonamido, mono or di(C.sub.1 -C.sub.6)alkylsulfonamido, 3,4-methylenedioxy, and 3,4-(1,2-ethylene)dioxy;


R.sub.2 is selected from C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl and haloalkyl;


R.sub.3 is hydrogen C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl;


R.sub.4 is C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl)C.sub.1-4 alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen,
nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino and mono- or di(C.sub.1 -C.sub.6)alkylamino,


R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, each of
which may be substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl,
1-pyrrolidinyl, 1-piperidyl,


R.sub.4 is a bicyclic oxygen-containing group of the formula: ##STR76##


 wherein R.sub.A represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono-
or di(C.sub.1 -C.sub.6)alkylamino;


Ar.sub.1 and Ar.sub.2 are independently chosen from i) phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl,
benzodioxolyl, and benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1
-C.sub.6)alkylaminocarbonyl, N--(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or ii) bicyclic oxygen-containing groups of the formula: ##STR77## wherein R.sub.B represents 0 to 3 groups selected from halogen,
nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Also preferred are compounds of formula XII wherein:


R, R.sub.2, R.sub.3, R.sub.4, and Ar.sub.2 are as defined in formula XII;


Ar.sub.1 is phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, and amino(C.sub.1 -C.sub.6)alkoxy.


Also preferred are compounds of formula XII wherein:


R, R.sub.2, and R.sub.3 are as defined in formula XII;


Ar.sub.1 is phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, and amino(C.sub.1 -C.sub.6)alkoxy;


R.sub.4 is C.sub.3 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3-8 cycloalkyl)C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.8 haloalkyl, each or which may be unsubstituted or substituted with
one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino and mono- or di(C.sub.1
-C.sub.6)alkylamino,


R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, each of
which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl;


Ar.sub.2 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d]isoxazolyl, each of
which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or


Ar.sub.2 is bicyclic oxygen-containing groups of the formula: ##STR78##


 wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono-
or di(C.sub.1 -C.sub.6)alkylamino.


Also preferred are compounds of formula XII wherein:


R is hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, or (C.sub.3 -C.sub.8)cycloalkyl) C.sub.1 -C.sub.3 alkyl, or


R is phenyl substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1
-C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino, aminocarbonyl, sufonamido, mono or di(C.sub.1 -C.sub.6)alkylsulfonamido, 3,4-methylenedioxy, and 3,4-(1,2-ethylene)dioxy;


R.sub.2 is C.sub.3 -C.sub.6 alkyl;


R.sub.3 is hydrogen, methyl, or ethyl;


R.sub.4 is C.sub.3 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3-8 cycloalkyl)C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.8 haloalkyl, each or which may be unsubstituted or substituted with
one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino and mono- or di(C.sub.1
-C.sub.6)alkylamino,


R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, each of
which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl;


Ar.sub.1 is phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, and amino(C.sub.1 -C.sub.6)alkoxy;


Ar.sub.2 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d]isoxazolyl, each of
which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or


Ar.sub.2 is bicyclic oxygen-containing groups of the formula: ##STR79##


 wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono-
or di(C.sub.1 -C.sub.6)alkylamino.


Also preferred are compounds of formula XII wherein:


R is hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, or (C.sub.3 -C.sub.8)cycloalkyl) C.sub.1 -C.sub.3 alkyl, or phenyl;


R.sub.2 is C.sub.3 -C.sub.6 alkyl;


R.sub.3 is hydrogen, methyl, or ethyl;


R.sub.4 is C.sub.3 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3-8 cycloalkyl)C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.8 haloalkyl, each or which may be unsubstituted or substituted with
one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino and mono- or di(C.sub.1
-C.sub.6)alkylamino;


Ar.sub.1 is phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, and amino(C.sub.1 -C.sub.6)alkoxy; and


Ar.sub.2 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d]isoxazolyl, each of
which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or


Ar.sub.2 is bicyclic oxygen-containing groups of the formula: ##STR80##


 wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Also preferred are compounds of formula XII wherein:


R is hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, or (C.sub.3 -C.sub.8)cycloalkyl) C.sub.1 -C.sub.3 alkyl, or phenyl;


R.sub.2 is C.sub.3 -C.sub.6 alkyl;


R.sub.3 is hydrogen, methyl, or ethyl;


R.sub.4 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, each of
which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl;


Ar.sub.1 is phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1
-C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, and amino(C.sub.1 -C.sub.6)alkoxy;


Ar.sub.2 is phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d]isoxazolyl, each of
which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
-C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or


Ar.sub.2 is bicyclic oxygen-containing groups of the formula: ##STR81##


 wherein R.sub.B represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy,
amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


The invention also includes compounds of the following formula XIII: ##STR82##


or a pharmaceutically acceptable salt thereof, wherein:


n is 1, 2, or 3 ##STR83##


 represents a carbon chain that may be substituted with hydrogen, halogen, cyano, nitro amino, mono or dialkyl amino, alkenyl, alkynyl, alkoxy, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl, or cycloalkyl, and n is 1, 2, or
3;


Ar.sub.1, Ar.sub.2, and Ar.sub.3 are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and
from 1 to 3 heteroatoms; and


R.sub.1 represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, hydroxy carbonyl (COOH),
aminocarbonyl (CONH.sub.2), mono or dialkylaminocarbonyl, sulfonamido, and mono or dialkylsulfonamido.


Also preferred are compounds of formula XIII wherein n, m, and R.sub.1 are defined as for formula XIII above;


Ar.sub.1 and Ar.sub.3 are independently chosen from phenyl, pyridyl, and pyrimidinyl each of which is optionally optionally substituted or substituted with up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C.sub.1
-C.sub.6 alkoxy, acetoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, C.sub.1 -C.sub.6 haloalkyl, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1
-C.sub.3 alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH.sub.2), mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or di(C.sub.1 -C.sub.6)alkylsulfonamido; and


Ar.sub.2 represents suberanyl, indanyl, tetrhydronaphtyl, or indolyl, each of which is optionally optionally substituted or substituted with up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy,
acetoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, C.sub.1 -C.sub.6 haloalkyl, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl,
hydroxy carbonyl (COOH), aminocarbonyl (CONH.sub.2), mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or di(C.sub.1 -C.sub.6)alkylsulfonamido.


Also preferred are compounds of formula XIII above wherein: ##STR84##


R.sub.1, R.sub.3, and R.sub.5 each represent up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, acetoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, C.sub.1 -C.sub.6 haloalkyl, C.sub.1
-C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH.sub.2), mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl,
sulfonamido, and mono or di(C.sub.1 -C.sub.6)alkylsulfonamido; and represents suberanyl, indanyl, tetrhydronaphtyl, or indolyl, each of which is optionally optionally substituted or substituted with up to 4 groups independently chosen from hydrogen,
halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, acetoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, C.sub.1 -C.sub.6 haloalkyl, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl,
(C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH.sub.2), mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or di(C.sub.1 -C.sub.6)alkylsulfonamido.


The invention also includes compounds of the followinf formula XIV: ##STR85##


or a pharmaceutically acceptable salt, thereof, wherein:


R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, hydroxy carbonyl (COOH),
aminocarbonyl (CONH.sub.2), mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or dialkylsulfonamido;


R.sub.1 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally substituted; or R.sub.1 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted heteroarylalkyl, or an optionally substituted heteroalicyclic or heteroalicyclicalkyl group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and


Ar.sub.1 and Ar.sub.2 are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, or an optionally substituted heteroalicyclic or
heteroalicyclicalkyl group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.


Preferred compounds of formula XIV include those (referred to herein as compounds of formula XIV-A) wherein


R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, acetoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, C.sub.1 -C.sub.6 haloalkyl, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6
alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl) C.sub.1 -C.sub.3 alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH.sub.2), mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy,
ethylenedioxy, and mono or di(C.sub.1 -C.sub.6)alkylsulfonamido;


R.sub.1 is C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl) C.sub.1-4 alkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino and mono- or di(C.sub.1 -C.sub.6)alkylamino, or


R.sub.1 is phenyl, phenylalkyl, chromanyl, chromanylalkyl, imidazolyl, imidazolylalkyl, pyridyl, pyridylalkyl, pyrimidyl, pyrimdylalkyl, pyrazinyl, pyrazinylalkyl, indolyl, indolylalkyl, indanyl, indanylalkyl, benzodioxolylalkyl, or
benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1
-C.sub.6)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl;


Ar.sub.1 is chosen from phenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, and pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, amino(C.sub.1 -C.sub.6)alkoxy, carboxylic acid, esters
of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, and N--(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl; and


Ar.sub.2 is chosen from phenyl, phenylalkyl, chromanyl, chromanylalkyl, pyrrolyl, pyrrolylalkyl, furanyl, furanylalkyl, thienyl, thienylalkyl, pyridyl, pyridylalkyl, pyrimidyl, pyrimidylalkyl, pyrazinyl, pyrazinylalkyl, benzimidazolyl,
benzimidazolylalkyl, imidazopyrdinyl, imidazopyrdinylalkyl, naphthyl, napthylalkyl, indolyl, indolylalkyl, indanyl, indanylalkyl, benzofuranyl, benzofuranylalkyl, benzodioxinyl, benzodioxinylalkyl, benzodioxolyl, benzodioxolylalkyl, quinolinyl,
quinolinylalkyl, isoquinolinyl, isoquinolinylalkyl, each of which may be optionally substituted or substituted with up to four groups independently selected from: halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,
C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino, mono- or di(C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)alkyl, amino(C.sub.1 -C.sub.6)alkoxy, C.sub.1 -C.sub.6 alkoxy
C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy C.sub.1 -C.sub.6 alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.sub.1 -C.sub.6)alkylaminocarbonyl, N--(C.sub.1 -C.sub.6)alkylsulfonylaminocarbonyl, benzyl (which may be
unsubstituted or substituted with one or more substituents independently chosen from halogen, C.sub.1 -C.sub.6 alkyl, and C.sub.1 -C.sub.6 alkoxy), --C.sub.1 -C.sub.6 alkyl NR.sub.2 R.sub.3 or --C.sub.1 -C.sub.6 alkoxy NR.sub.2 R.sub.3 wherein the point
of attachment to Ar.sub.2 is at the C.sub.1 -C.sub.6 alkyl or C.sub.1 -C.sub.6 alkoxy, and R.sub.2 and R.sub.3 are hydrogen, or straight or branched chain alkyl and are optionally substituted with halogen, hydroxy, or C.sub.1 -C.sub.6 alkoxy and R.sub.2
and R.sub.3 may be taken together with the nitrogen to which they are attached to form a heterocycloalkyl group.


Preferred compopunds of formula XIV-A include those wherein: ##STR86##


wherein


Ar.sub.2 is as defined in Claim in formula XIV-A;


R.sub.X represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, acetoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, C.sub.1 -C.sub.6 haloalkyl, C.sub.1 -C.sub.6 alkyl, C.sub.2
-C.sub.6 alkenyl, and C.sub.2 -C.sub.6 alkynyl; and


R.sub.1 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl)C.sub.1 -C.sub.4 alkyl, phenyl, phenyl C.sub.1 -C.sub.6 alkyl, chromanyl, chromanyl C.sub.1 -C.sub.6 alkyl, imidazolyl, imidazolyl C.sub.1 -C.sub.6
alkyl, pyridyl, pyridyl C.sub.1 -C.sub.6 alkyl, pyrimidyl, pyrimidyl C.sub.1 -C.sub.6 alkyl, pyrazinyl, pyrazinyl C.sub.1 -C.sub.6 alkyl, indolyl, indolyl C.sub.1 -C.sub.6 alkyl, indanyl, indanyl C.sub.1 -C.sub.6 alkyl, benzodioxolyl, or benzodioxolyl
C.sub.1 -C.sub.6 alkyl each or which may be unsubstituted or substituted with up to 4 substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1 -C.sub.6 alkoxy, amino and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Additional preferred compounds of formula XIV-A includes those of the following formula: ##STR87##


wherein:


R.sub.X represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy substituted with 0-2 R.sub.2, acetoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, C.sub.1 -C.sub.6 haloalkyl,
C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, and C.sub.2 -C.sub.6 alkynyl;


R.sub.1 is phenyl, phenyl C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl(C.sub.1 -C.sub.4 alkyl), naphthyl, napthyl C.sub.1 -C.sub.6 alkyl, indanyl, indanyl C.sub.1 -C.sub.6 alkyl, benzodioxolanyl, or
benzodioxolanyl C.sub.1 -C.sub.6 alkyl, each of which may be substituted by up to 4 groups chosen from halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, acetoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, C.sub.1 -C.sub.6 haloalkyl, C.sub.1
-C.sub.6 alkyl; and


Ar.sub.2 represents phenyl, benzyl, indanyl, indanyl-CH.sub.2 --, benzodioxolanyl, or benzodioxolanyl-CH.sub.2 --; each of which is substituted by up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6
alkoxy, acetoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, C.sub.1 -C.sub.6 haloalkyl, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, and C.sub.2 -C.sub.6 alkynyl.


Additional preferred compounds of formula XIV includes those wherein:


Ar.sub.2 is as defined for formula XIV;


R represents up to 4 groups independently chosen from hydrogen, halogen, amino, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, trifluoromethyl, and trifluoromethoxy;


R.sub.1 is phenyl, benzyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl(C.sub.1 -C.sub.4 alkyl), naphthyl, naphthyl-CH.sub.2 --, indanyl, indandyl-CH.sub.2 --, benzodioxolanyl-CH.sub.2 --, or benzodioxolanyl, each of which may be
substituted by up to 4 groups chosen from halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, acetoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, C.sub.1 -C.sub.6 haloalkyl, C.sub.1 -C.sub.6 alkyl; and


Ar.sub.1 is chosen from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, C.sub.1
-C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, and amino.


Also preferred are compounds of the formula XIV above wherein:


R represents up to 4 groups independently chosen from hydrogen, halogen, amino, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, trifluoromethyl, and trifluoromethoxy;


R.sub.1 is benzyl which is unsubstituted or substituted by up to 4 groups chosen from halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, acetoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, C.sub.1 -C.sub.6 haloalkyl, C.sub.1 -C.sub.6
alkyl;


Ar.sub.1, is chosen from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, C.sub.1
-C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkyl, and amino; and


Ar.sub.2 is chosen from phenyl, benzyl, indolyl, indolyl-CH.sub.2 --, indanyl, indanyl-CH.sub.2 --, chromanyl, chromanyl-CH.sub.2 --, benzofuranyl, benzofuranyl-CH.sub.2 --, benzodioxinyl, benzodioxinyl-CH.sub.2 --, benzodioxolyl-CH.sub.2 --, and
benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from: halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1 -C.sub.6 alkoxy, amino, and mono- or di(C.sub.1 -C.sub.6)alkylamino.


Preferred compounds of formula XIV also include thos eof the following formula IV-B: ##STR88##


wherein:


m is 0, 1, 2, or 3, and ##STR89##


 represents a carbon chain which is optionally substituted with methyl, ethyl, methoxy, ethoxy, hydoxy, halogen, or amino;


R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, acetoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino;


R.sub.X and R.sub.Y each represent up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, acetoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, C.sub.1 -C.sub.6 haloalkyl, C.sub.1 -C.sub.6
alkyl, C.sub.2 -C.sub.6 alkenyl, and C.sub.2 -C.sub.6 alkynyl; and


R.sub.1 and R.sub.4 are independently selected from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, (C.sub.3 -C.sub.8 cycloalkyl)C.sub.1 -C.sub.4 alkyl, phenyl, phenyl C.sub.1 -C.sub.6 alkyl, pyridyl, and pyridyl C.sub.1 -C.sub.6 alkyl, each
or which may be unsubstituted or substituted with up to 4 substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl,
C.sub.1 -C.sub.6 alkoxy, amino and mono- or di(C.sub.1 -C.sub.6)alkylamino.


The invention also provides compounds of the following formula XV: ##STR90##


or a pharmaceutically acceptable salt thereof, wherein;


m is 0, 1, 2, or 3, and ##STR91##


 presents a carbon chain which is optionally substituted with methyl, ethyl, methoxy, ethoxy, hydoxy, halogen, or amino;


n is 0, 1, 2, or 3, and ##STR92##


 represents a carbon chain which is optionally substituted with methyl, ethyl, methoxy, ethoxy, hydoxy, halogen, or amino;


R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl;


R.sub.2 is i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl) alkyl, each of which may be unsubstituted or substituted by one or more of
halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, mono- or dialkylamino; and


Ar.sub.1 and Ar.sub.2 are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkyl, or an optionally
substituted heteroalicyclic or heteroalicyclicalkyl group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.


Preferred compounds of formula XV include those of the following formula:


m is 1 and ##STR93##


 represents a carbon chain which is unsubstituted;


n is 1 and ##STR94##


 represents a carbon chain which is unsubstituted;


R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C.sub.1 -C.sub.6 alkoxy, acetoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino, cyano, nitro, C.sub.1 -C.sub.6 haloalkyl, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6
alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.2 -C.sub.6 cycloalkyl, and (C.sub.3 -C.sub.8 cycloalkyl)C.sub.1 -C.sub.4 alkyl;


R.sub.2 is C.sub.3 -C.sub.8 alkyl or C.sub.3 -C.sub.8 cycloalkyl;


Ar.sub.1 and Ar.sub.2 are independently chosen from phenyl, phenyl(C.sub.1 -C.sub.4)alkyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl, and pyrazinyl, each of which may be unsubstituted or optionally
substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1
-C.sub.6 alkoxy, amino, mono- or di(C.sub.1 -C.sub.6)alkylamino.


Compounds of the invention may have one or more asymmetric centers or planes.  Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms.  It is well known in the art how
to prepare optically active forms, such as by resolution of racemic forms (racemates), by asymmetric synthesis, or by synthesis from optically active starting materials.  Resolution of the racemates can be accomplished, for example, by conventional
methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.  Many geometric isomers of olefins, C.dbd.N double bonds, and the like can also be present in the compounds described
herein, and all such stable isomers are contemplated in the present invention.  Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.  All
chiral (enantiomeric and diastereomeric), and racemic forms, as well as all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.


Some compounds of the invention may exist as tautomers.  Unless otherwise specified any description or claim of one tautomeric form is intended to encompass the other tautomer.


Specifically preferred compounds include those shown in the FIGS. 1 through 6.  In those figures, the substituent X depicts the moiety linkage to the base compound whose strucutre is shown at the top of each Figure.


Addiional preferred compounds of the invention include the following (compounds structures are shown directly above the compound chemical name in many instances):


1-(1-butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenyl methyl])aminomethylimidazole;


1-(1-butyl)-2-phenyl-5-(1-[N-{3,4-methylenedioxyphenylmethyl}-N-phenylmethy l]amino)ethylimidazole;


1-Butyl-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[1-butyl])aminomethylimidazole ;


1-(1-Butyl)-2-phenyl-4-methyl-5-(N-[3,4-methylenedioxyphenyl-methyl]-N-phen ylmethyl)aminomethylimidazole;


1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[1,4-benzodioxan-6-yl]methyl-N-phenylme thyl)aminomethylimidazole;


1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phen ylmethyl)aminomethylimidazole;


1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[1,4-benzodioxan-6-yl]methyl-N-phenylme thyl)aminomethylimidazole; ##STR95##


1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phen ylmethyl)aminomethylimidazole; ##STR96##


1-(1-Butyl)-2-(2-fluorophenyl)-5-(N-[1,4-benzodioxan-6-ylmethyl]-N-phenylme thyl)amino-methylimidazole; ##STR97##


1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N-[naphtha-2-ylmethyl]-N-phenylmethyl)am ino-methylimidazole; ##STR98##


1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phe nylmethyl)aminomethylimidazole; ##STR99##


1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])a minomethylimidazole; ##STR100##


1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N-[4-dimethylaminophenylmethyl]-N-phenyl methyl)aminomethylimidazole; ##STR101##


1-(1-Butyl)-2-(2-methylphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phen ylmethyl)aminomethylimidazole; ##STR102##


1-(1-Butyl)-2-(4-fluorophenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])am ino-methylimidazole; ##STR103##


1-(1-Butyl)-2-(2-methylphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])am ino-methylimidazole; ##STR104##


1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[naphth-2-ylmethyl]-N-phenylmethyl)amin omethylimidazole; ##STR105##


1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phen ylmethyl)aminomethylimidazole; ##STR106##


1-(1-Butyl)-2-(3-fluorophenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])am ino-methylimidazole; ##STR107##


1-(1-Butyl)-2-(3-methoxyphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phe nylmethyl)-aminomethylimidazole; ##STR108##


1-(1-Butyl)-2-phenyl-5-{1-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethy l)amino}ethylimidazole; ##STR109##


1-(1-Pentyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl)aminomethylimi dazole; ##STR110##


Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethy l)-amine ##STR111##


Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-5-(4-methoxy-phenyl)-2-phenyl-3 H-imidazol-4-ylmethyl]-amine ##STR112##


4-({Benzyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amino}-methyl) -benzamide ##STR113##


4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-3-c hlorophenol ##STR114##


4-({[1-(3-Butyl-2-phenyl-3H-imidazol-4-yl)-pentyl]-cyclohexylmethyl-amino}- methyl)-phenol ##STR115##


4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-ben zamide ##STR116##


1-(1-Propyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl)aminomethylimi dazole; ##STR117##


1-(1-Butyl)-2-phenyl-5-(N-[1-(S)-phenylethyl]-N-phenylmethyl)aminomethylimi dazole; ##STR118##


1-(1-Butyl)-2-phenyl-5-(N-[1-(R)-phenylethyl]-N-phenylmethyl)aminomethylimi dazole; ##STR119##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dichlorop henyl]methyl)aminomethylimidazole; ##STR120##


1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenylmethyl])aminomethyli midazole; ##STR121##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-methoxyph enylmethyl])-aminomethylimidazole; ##STR122##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{1-propyl}p henylmethyl])aminomethylimidazole; ##STR123##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dichlorop henylethyl])aminomethylimidazole; ##STR124##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[4-nitrophenyl methyl])aminomethylimidazole; ##STR125##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{1-propylox y}phenylmethyl])aminomethylimidazole; ##STR126##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[quinol-6-ylme thyl])-aminomethylimidazole; ##STR127##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2,3-dichlorop henylmethyl])-aminomethylimidazole; ##STR128##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dimethylp henylmethyl])-aminomethylimidazole; ##STR129##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[indan-2-yl])- aminomethylimidazole; ##STR130##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2-phenylethyl ])amino-methylimidazole; ##STR131##


1-(1-Propyl)-2-phenyl-5-(N-[1,4-benzodioxan-6-ylmethyl]-N-phenylmethyl)amin omethyl-imidazole; ##STR132##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)a minomethyl-imidazole; ##STR133##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-ethyl)aminomet hylimidazole; ##STR134##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-propyl])ami nomethyl-imidazole; ##STR135##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-butyl])amin omethyl-imidazole; ##STR136##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cycloheptylmet hyl)amino-methylimidazole; ##STR137##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-isobutyl)amino methyl-imidazole; ##STR138##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2-cyclopentyl ethyl])amino-methylimidazole; ##STR139##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3-cyclopentyl propyl])amino-methylimidazole; ##STR140##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-n-octyl])am inomethyl-imidazole; ##STR141##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclopropylmet hyl)amino-methylimidazole; ##STR142##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclopentylmet hyl)amino-methylimidazole; ##STR143##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclohexylmeth yl)amino-methylimidazole; ##STR144##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[t-amyl])amino methylimidazole; ##STR145##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-{3-methyl}b utyl)]amino-methylimidazole; ##STR146##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-{2,2-dimeth yl}butyl])aminomethylimidazole; ##STR147##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-methyl)aminome thylimidazole; ##STR148##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2-thiophenylm ethyl])amino-methylimidazole; ##STR149##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[indol-5-ylmet hyl])amino-methylimidazole; ##STR150##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[{1-methylindo l-5-yl}methyl])aminomethylimidazole; ##STR151##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[4-hydroxy-2-c hlorophenyl]-methyl)aminomethylimidazole; ##STR152##


1-(1-Butyl)-2-(3-fluorophenyl)-5-(1-[N-{2-chloro-4-hydroxyphenyl}methyl-N-p henylmethyl])aminoethylimidazole; ##STR153##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[2,3-dihydrobe nzo[b]furan-5-yl]methyl)aminomethylimidazole; ##STR154##


1-Butyl-2-(4-fluorophenyl)-5-(1-[N-{3,4-methylenedioxyphenyl}methyl-N-pheny lmethyl]amino)ethylimidazole; ##STR155##


1-(1-Butyl)-2-(2-thienyl)-5-(N-[3,4-methylenedioxyphenyl]methyl-N-phenylmet hyl]aminomethylimidazole; ##STR156##


1-(1-Butyl)-2-phenyl-5-(N-[3,4,5-trimethoxyphenylmethyl]-N-phenylmethyl)ami nomethylimidazole; ##STR157##


1-(1-Butyl)-2-phenyl-5-(N-phenylmethyl-N-[3,4-dimethoxyphenylmethyl])aminom ethylimidazole; ##STR158##


1-(1-Butyl)-2-phenyl-5-(N-[4-dimethylaminophenylmethyl]-N-phenylmethyl)amin omethyl-imidazole; ##STR159##


1-(1-Butyl)-2-phenyl-5-(N-[4-methylaminophenylmethyl]-N-phenylmethyl)aminom ethyl-imidazole; ##STR160##


1-(1-Butyl)-2-phenyl-5-(N-[3-methyl-4-aminophenylmethyl]-N-phenylmethyl)ami nomethyl-imidazole); ##STR161##


1-(1-Butyl)-2-phenyl-5-(N-[2,3-dichlorophenylmethyl]-N-phenylmethyl)aminome thylimidazole; ##STR162##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-dichlorophenyl methyl]-N-phenylmethyl)amninomethylimidazole; ##STR163##


1-(1-Butyl)-2-phenyl-5-(N-[3,4-difluorophenylmethyl]-N-phenylmethyl)aminome thylimidazole; ##STR164##


1-(1-Butyl)-2-phenyl-5-(N-(benzo[b]thiophen-5-ylmethyl)-N-phenylmethyl)amin omethylimidazole; ##STR165##


1-(1-Butyl)-2-phenyl-5-(N-[4-ethoxyphenylmethyl]-N-phenylmethyl)aminomethyl imidazole; ##STR166##


1-(1-Butyl)-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[1-butyl])aminomethylimida zole; ##STR167##


1-(1-Butyl)-2-phenyl-5-(N-[4-methoxyphenylmethyl]-N-phenylmethyl)aminomethy limidazole; ##STR168##


1-(1-Butyl)-2-phenyl-5-(N-[6-chloro-3,4-methylenedioxyphenylmethyl]-N-pheny lmethyl)-aminomethylimidazole; ##STR169##


1-(1-Butyl)-2-phenyl-5-(N-[2,3-dichlorophenylmethyl]-N-[1-butyl])aminomethy limidazole; ##STR170##


1-(1-Butyl)-2-phenyl-5-(N-[3-methoxyphenylmethyl]-N-phenylmethyl)aminomethy limidazole; ##STR171##


1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-4-fluorophenylmethyl]-N-phenylmethyl)am inomethyl-imidazole; ##STR172##


1-(1-Butyl)-2-phenyl-4-bromo-5-(N-[2,3-dichlorophenylmethyl]-N-[1-butyl])am inomethyl-imidazole; ##STR173##


1-(1-Butyl)-2-phenyl-5-(N-[2,6-dichlorophenylmethyl]-N-phenylmethyl)aminome thylimidazole; ##STR174##


1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N-phenylmethyl)a minomethyl-imidazole; ##STR175##


1-(1-Butyl)-2-phenyl-4-chloro-5-(N-phenylmethyl-N-[1-butyl])aminomethylimid azole; ##STR176##


4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-2-m ethyl-phenol ##STR177##


4-{[(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-cyclohexylmethyl-amino]-m ethyl}-2-methyl-phenol ##STR178##


(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(2,6-difluoro-benzyl)-(4-meth oxy-benzyl)amine ##STR179##


Benzo[1,3]dioxol-5-ylmethyl-butyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl-3H -imidazol-4-ylmethyl]-amine ##STR180##


4-({Benzyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl-3H-imidazol-4-ylmethyl]-a mino}-methyl)benzenesulfonamide ##STR181##


Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl-3 H-imidazol-4-ylmethyl]-amine ##STR182##


4-({Butyl-[3-butyl-2-(3-methoxy-phenyl)-5-phenyl-3H-imidazol-4-ylmethyl]-am ino}-methyl)-3-chloro-phenol ##STR183##


2-4-{[(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(4-methoxy-benzyl)-amin o]-methyl}-benzoic acid ##STR184##


4-({Benzyl-[3-butyl-2-3-methoxy-phenyl)-5-phenyl-3H-imidazol-4-ylmethyl]-am ino}-methyl)-3-chloro-phenol ##STR185##


Benzo[1,3]dioxol-5-ylmethyl-benzyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-y l)-pentyl]-amine ##STR186##


Benzo[1,3]dioxol-5-ylmethyl-benzyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-y l)-ethyl]-amine ##STR187##


4-{[Butyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-benz amide ##STR188##


Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-5-(4-fluoro-phenyl)-2-phenyl-3H -imidazol-4-ylmethyl]-amine ##STR189##


3-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-phe nol ##STR190##


4-{[Butyl-(3-butyl-5-tert-butyl-2-phenyl-3H-imidazol-4-ylmethyl)-amino]-met hyl}-benzamide ##STR191##


Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(2,3-dihydro-benzo[1,4 ]dioxin-6-ylmethyl)-amin ##STR192##


(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(2,5-difluoro-benzyl)-(4-meth oxy-benzyl)-amine ##STR193##


(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(2,6-difluoro-benzyl)-(4-meth oxy-benzyl)-amine ##STR194##


4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-2,6 -dimethyl-phenol ##STR195##


4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohex ylmethyl-amino}-methyl)-2,6-dimethyl-phenol ##STR196##


[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohexylme thyl-(2,3-dihydro-benzofuran-5-ylmethyl)-amine ##STR197##


4-{[Butyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-2,6- dimethyl-phenol ##STR198##


4-({Butyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amino}-methyl)- 2,6-dimethyl-phenol ##STR199##


4-{[(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(4-dimethylamino-benzyl)- amino]-methyl}-benzoic acid ##STR200##


4-{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-2,4-diphenyl-imidazol -1-yl}-butyric acid ethyl ester ##STR201##


4-{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-2,4-diphenyl-imidazol -1-yl}-butan-1-ol ##STR202##


(4-{[(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-cyclohexylmethyl-amino]- methyl}-phenyl)-dimethyl-amine ##STR203##


1-(1-Butyl)-2-phenyl-5-(N-[4-{1-pyrrolidinyl}phenylmethyl]-N-phenylmethyl)a minomethyl-imidazole; ##STR204##


1-(1-Butyl)-2-phenyl-5-(N-[4-diethylaminophenylmethyl]-N-phenylmethyl)amino methyl-imidazole; ##STR205##


1-(1-Butyl)-2-phenyl-5-(N-[pyridin-2-ylmethyl]-N-phenylmethyl)aminomethylim idazole; ##STR206##


1-(1-Butyl)-2-phenyl-5-(N-[pyridin-3-ylmethyl]-N-phenylmethyl)aminomethylim idazole; ##STR207##


1-(1-Butyl)-2-phenyl-5-(N-[pyridin-4-ylmethyl]-N-phenylmethyl)aminomethylim idazole; ##STR208##


1-(1-Butyl)-2-phenyl-5-(N-[2-fluoro-6-chlorophenylmethyl]-N-phenylmethyl)am inomethyl-imidazole); ##STR209##


1-(1-Butyl)-2-phenyl-5-(N-[2,4-dichlorophenylmethyl]-N-phenylmethyl)aminome thyl-imidazole); ##STR210##


1-(1-Butyl)-2-phenyl-5-(N-[4-chlorophenylmethyl]-N-phenylmethyl)aminomethyl imidazole; ##STR211##


1-(1-Butyl)-2-phenyl-5-(N-[4-hydroxyphenylmethyl]-N-phenylmethyl)aminomethy limidazole; ##STR212##


1-(1-Butyl)-2-phenyl-5-(N-[4-trifluoromethoxyphenylmethyl]-N-phenylmethyl)a minomethyl-imidazole); ##STR213##


1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-3,4-dimethoxyphenylmethyl]-N-phenylmeth yl)amino-methylimidazole); ##STR214##


1-(1-Butyl)-2-phenyl-5-(N-[4-nitrophenylmethyl]-N-phenylmethyl)aminomethyli midazole; ##STR215##


1-(1-Butyl)-2-phenyl-5-(N-[4-aminophenylmethyl)-N-phenylmethyl)aminomethyli midazole; ##STR216##


1-(1-Butyl)-2,4-diphenyl-5-(N-phenylmethyl-N-[1-butyl])aminomethylimidazole ; ##STR217##


1-(1-Butyl)-2-phenyl-5-(N-[2-aminopyridin-5-ylmethyl]-N-phenylmethyl)aminom ethyl-imidazole ##STR218##


1-(1-Butyl)-2-phenyl-5-(N-[2,3-dihydrobenzo[b]furan-5-ylmethyl]-N-phenylmet hyl)amino-methylimidazole; ##STR219##


1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N-[1-butyl])amin omethylimidazole) ##STR220##


1-(1-Butyl)-2-phenyl-4-methyl-5-(N-phenylmethyl-N-[1-butyl])aminomethylimid azole; ##STR221##


1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N-phen ylmethyl)aminomethylimidazole; ##STR222##


1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N-phen ylmethyl)aminomethylimidazole; ##STR223##


1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[2,3-dichlorophenylmethyl]-N-phenylmeth yl)aminomethylimidazole; ##STR224##


1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[4-dimethylaminophenylmethyl]-N-phenylm ethyl)amino-methylimidazole; ##STR225##


1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[4-{1-pyrrolidinyl}phenylmethyl]-N-phen ylmethyl)amino-methylimidazole; ##STR226##


1-(1-Butyl)-2-(3-chlorophenyl)-5-(1-[N-{2-chloro-4-hydroxyphenylmethyl}-N-p henylmethyl]amino)ethylimidazole; ##STR227##


1-(1-Butyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl)aminomethylimid azole; ##STR228##


1-(1-Butyl)-2-(4-fluorophenyl)-5-(1-N,N-di[3,4-methylenedioxyphenylmethyl]a mino)ethylimidazole; ##STR229##


2-{[5-({Butyl[(1-butyl-2,4-diphenylimidazol-5-yl)methyl]amino}methyl)-2-pyr idyl]amino}ethan-1-ol;


As discussed above, preferred compounds of the invention exhibit good activity in standard in vitro C5 receptor mediated chemotaxis assay, specifically the assay as specified in Example 12, which follows.  References herein to "standard in vitro
C5 receptor mediated chemotaxis assay" are intended to refer to that protocol as defined in Example 12 which follows.  Preferred compound of the invention exhibit an EC.sub.50 of about 100 .mu.M or less in such a standard C5a mediated chemotaxis assay,
more preferably an EC.sub.50 of about 10 .mu.M or less in such a standard C5a mediated chemotaxis assay, still more preferably an EC.sub.50 of about 1 .mu.M in such a standard C5a mediated chemotaxis assay, even more preferably an EC.sub.50 of about 0.1
.mu.M in such a standard C5a mediated chemotaxis assay.


Additional assays suitable for determining the effects of small molecule compounds on C5a receptor binding and receptor modulatory activity, as well as assays suitable for measuring their effects on C5a-induced neutropenia in vivo, can be found
in the published literature, for example in U.S.  Pat.  No. 5,807,824, which is incorporated herein by reference for its disclosure in this regard in Examples 6-9, columns 19-23, as well as for its discussion of complement and inflammation at columns
1-2.  Those of skill in the art will recognize that such assays can be readily adapted to the use of cells or animals of different species as deemed appropriate.


In one aspect of the invention, one or more compounds of the invention, preferably in solution in a pharmaceutically acceptable carrier as a pharmaceutical preparation, is used to perfuse a donor organ prior to transplantation of the organ into a
recipient patient.  Such perfusion is preferably carried out using a solution comprising an concentration of the compound of thee invention that is an effective amount sufficient to inhibit C5a mediated effects in vitro or in vivo.  Such perfusion
preferably reduces the severity or frequency of one or more of the inflammatory sequelae following organ transplantation when compared to that occurring in control (including, without restriction, historical control) transplant recipients who have
received transplants of donor organs that have not been so perfused.


Definitions


In certain situations, the compounds of of the invention may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g. asymmetric carbon atoms, so that the compounds can exist in different
stereoisomeric forms.  These compounds can be, for example, racemates or optically active forms.  For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers.  In these situations, the single
enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis, synthesis from optically pure precursors or by resolution of the racemates.  Resolution of the racemates can be accomplished, for example, by conventional methods such as
crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.


The term "substituted", as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the
substitution results in a stable compound.  When a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced.  Keto substituents are not present on aromatic moieties.  The present invention is intended to include all isotopes of atoms
occurring in the present compounds.  Isotopes include those atoms having the same atomic number but different mass numbers.  By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon
include .sup.11 C, .sup.13 C, and .sup.14 C.


When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence.  Thus, for example, if a group is shown to be substituted with
0-2 R*, then said group may optionally be substituted with up to two R* groups and R* at each occurrence is selected independently from the definition of R*.  Also, combinations of substituents and/or variables are permissible only if such combinations
result in stable compounds.


As indicated herein, various substituents of the compounds of the present invention and various formulae set forth herein are "optionally substituted", including, e.g., Ar.sub.1, Ar.sub.2, R, R.sub.1, R.sub.2, R.sub.3, R.sub.3A, R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.A, R.sub.A ', R.sub.B, and R.sub.C.  When substituted, those substituents may be substituted at one or more of any of the available positions, typically 1, 2, 3, or 4 positions, by one or more suitable groups such as those
disclosed herein.


Suitable groups or "substituted" moities of compounds of the invention include e.g., halogen such as fluoro, chloro, bromo or iodo; cyano; hydroxyl; nitro; azido; alkanoyl such as a C.sub.1-6 alkanoyl group such as acyl and the like; carboxamido;
alkyl groups including those groups having 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon, or 2, 3, 4, 5 or 6 carbon
atoms; alkoxy groups having those having one or more oxygen linkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and
from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms; alkylsulfonyl groups
including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6
carbon atoms; carbocyclic aryl having 6 or more carbons, particularly phenyl (e.g. an Ar group being a substituted or unsubstituted biphenyl moiety); arylalkyl having 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms, with benzyl
being a preferred group; aralkoxy having 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms, with O-benzyl being a preferred group; or a heteroaromatic or heteroalicyclic group having 1 to 3 separate or fused rings with 3 to about 8
members per ring and one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl,
piperidinyl, morpholino and pyrrolidinyl.


As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms.  Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl,
i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.  Preferred alkyl groups are C.sub.1 -C.sub.8 and C.sub.1-6 alkyl groups.  Especially preferred alkyl groups are methyl, ethyl, propyl, butyl, 3-pentyl.  The term C.sub.1-6 alkyl as used herein
includes alkyl groups consisting of 1 to 6 carbon atoms, which may contain a cyclopropyl moiety.  Suitable examples are methyl or ethyl.


"Cycloalkyl" is intended to include saturated ring groups, having the specified number of carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl and brigded or caged saturated ring groups such as norbornane or adamantane and
the like.


In the term "(C.sub.3-6 cycloalkyl)C.sub.1-4 alkyl", as defined above, the point of attachment is on the alkyl group.  This term encompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.


"Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration comprising one or more unsaturated carbon-carbon bonds, which may occur in any stable point along the chain, such as ethenyl and propenyl.


"Alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration comprising one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl.


"Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example --C.sub.v (X.sup.i).sub.wi
(H.sub.2v+1-.SIGMA.(wi)) where v=1 to 3; X.sup.i =F(i=1), Cl(i=2), Br(i=3), I(i.times.4)and (i=4) and .SIGMA.w.sub.i.ltoreq.2v+1).  Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and
pentachloroethyl.


"Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.  Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy,
t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.


As used herein, the term "carbocyclic aryl" indicates aromatic groups containing only carbon in the aromatic ring.  Such aromatic groups may be further substituted with carbon or non-carbon atoms or groups.  Typical carbocyclic aryl groups
contain 1 to 3 separate of fused rings and from 6 to about 18 ring atoms, without heteroatoms as ring members.  Specifically preferred carbocyclic aryl groups include phenyl, napthyl, including 1-naphthyl and 2-naphthyl, and acenaphthyl.


By the term "energetically accessible conformer" is meant any conformer of a compound that falls within about a 15 Kcal/mol window above the lowest energy conformation (as for example that found in a monte carlo or systematic confirmational
search) by using MM2, MM3, or MMFF force fields as implemented in molecular modeling software such as MacroModel.RTM.  v 7.0, Schrodinger, Inc., Portland, Ore.  United Stats and Jersey City, N.J., United States, http://www.schrodinger.com or the like.


Peptidomimetic compounds are generally compounds with "chemical structures derived from bioactive peptides which imitate natural molecules" (Murray Goodman and Seonggu Ro, "Peptidomimetics for Drug Design" chapter twenty in Burger's Medicinal
Chemistry and Drug Discovery, Volume 1: Principles and Practice, Manfred E. Wolff, ed.  John Wiley & Sons, Inc., NY, 1995, pp.  801-861.) As used herein and in the claims, the term peptidomimetic additionally comprises peptoid compounds, which are
compounds that comprise oligomers of N-substituted natural amino acids, and the term further comprises any compound having more than two amide bonds.


As used herein, the terms "heteroaryl" and "heteroalicyclic" group are intended to indicate a stable 5-to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated
(aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. 
The term heteroaryl indicates that the group contains at least 1 aromatic ring.  The nitrogen and sulfur heteroatoms may optionally be.  oxidized.  The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results
in a stable structure.  The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.  A nitrogen in the heterocycle may optionally be quaternized.


It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms .are not adjacent to one another.  It is preferred that the total number of S and O atoms in the heterocycle is not more than 1, 2,
or 3, more typically 1 or 2.  It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.


Examples of heteroaryl groups and other heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,
imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,
pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyi,
thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.


Preferred heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, furanyl, and thienyl.  Also included are fused ring and Spiro compounds containing, for example, the above heterocycles.


The term "halogen" indicates fluorine, chlorine, bromine, or iodine.


The term "pharmaceutically acceptable salts" includes, but is not limited to non-toxic salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrite or salts with an organic acids such as malate,
maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, salicylate and stearate.  Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium,
calcium, aluminum, lithium and ammonium.  The present invention also encompasses the prodrugs of the compounds disclosed.


Examples of bicyclic oxygen containing groups of the formula: ##STR230##


(R.sub.A may also be indicated R.sub.B) include the following: ##STR231##


Methods of Treating Patients


The present invention provides methods of treating patients suffering from diseases or disorders involving pathologic activation of C5a receptors.  Such diseases and disorders may include the following.


Such disorders that may be autoimmune in nature and are suitable for treatment in accordance with the present invention include e.g. rheumatoid arthritis, systemic lupus erythematosus (and associated glomerulonephritis), psoriasis, Crohn's
disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome (and associated
glomerulonephritis and pulmonary hemorrhage), and immunovasculitis.  Such inflammatory and related conditions include neutropenia, sepsis, septic shock, Alzheimer's disease, stroke, inflammation associated with severe burns, lung injury, myocardial
infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, artherosclerosis, traumatic central nervous system injury and ischemic heart disease, and ischemia-reperfusion injury, as well as acute (adult) respiratory distress
syndrome (ARDS), systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), tissue graft rejection, and hyperacute rejection of transplanted organs.  Also included are pathologic sequellae associated with
insulin-dependent diabetes mellitus (including diabetic retinopathy), lupus nephropathy, Heyman nephritis, membranous nephritis and other forms of glomerulonephritis, contact sensitivity responses, and inflammation resulting from contact of blood with
artificial surfaces that can cause complement activation, as occurs, for example, during extracorporeal circulation of blood (e.g., during hemodialysis or via a heart-lung machine, for example, in association with vascular surgery such as coronary artery
bypass grafting or heart valve replac ement) such as extracorporeal post-dialysis syndrome, or in association with contact with other artificial vessel or container surfaces (e.g., ventricular assist devices, artificial heart machines, transfusion
tubing, blood storage bags, plasmapheresis, plateletpheresis, and the like).


Treatment methods of the invention include in general administration to a patient a therapeutically effective amount of one or more compounds of the invention.  Suitable patients include those subjects suffering from or susceptible to (i.e.
propylactic treatment) a disorder or disease identified herein.  Typical patients for treatment in accordance with the invention include mammals, particularly primates, especially humans.  Other suitable subjects include domesticated companion animals
such as a dog, cat, horse, and the like, or a livestock animal such as cattle, pig, sheep and the like.


Pharmaceutical Preparations


The compounds of the invention may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. 
Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred.  The term parenteral as used herein includes injections and the like, such as subcutaneous, intradermal, intravascular (e.g.,
intravenous), intramuscular, intrasternal, spinal, intrathecal, and like injection or infusion techniques, with subcutaneous, intramuscular and intravascular injections or infusions being preferred.  In addition, there is provided a pharmaceutical
formulation comprising a compound of the invention and a pharmaceutically acceptable carrier.  One or more compounds of the invention may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or
adjuvants and if desired other active ingredients.  The pharmaceutical compositions containing compounds of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders
or granules, emulsion, hard or soft capsules, or syrups or elixirs.


Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.  Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are
suitable for the manufacture of tablets.  These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch,
or alginic acid; binding agents, for example.  starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.  The tablets may be uncoated or they may be coated by known techniques to delay disintegration and
absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.  For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.


Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the
active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.


Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.  Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose,
hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty
acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids
and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.  The aqueous suspensions may also
contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.


Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.  The oily suspensions may contain a thickening
agent, for example beeswax, hard paraffin or cetyl alcohol.  Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations.  These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.


Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.  Suitable
dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.  Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.


Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.  The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. 
Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for
example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.  The emulsions may also contain sweetening and flavoring agents.


Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.  Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.  The pharmaceutical
compositions may be in the form of a sterile injectable aqueous or oleaginous suspension.  This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned
above.  The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.  Among the acceptable vehicles and solvents that may be
employed are water, Ringer's solution and isotonic sodium chloride solution.  In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.  For this purpose any bland fixed oil may be employed including synthetic mono-
or diglycerides.  In addition, fatty acids such as oleic acid find use in the preparation of injectables.


The compounds of the invention may also be administered in the form of suppositories e.g., for rectal administration of the drug.  These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at
ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.  Such materials are cocoa butter and polyethylene glycols.


Compounds of the invention may be administered parenterally, preferably in a sterile non-toxic, pyrogen-free medium.  The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.  Advantageously,
adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.


Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are.useful in the treatment or preventions of conditions involving pathogenic C5a activity, particularly those disorders list in the "background
of the invention" section (about 0.5 mg to about 7 g per patient per day).  The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode
of administration.  Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.


Frequency of dosage may also vary depending on the compound used and the particular disease.  treated.  However, for treatment of most disorders, a dosage regimen of 4 times daily, three times daily, or less is preferred, with a dosage regimen of
once daily or 2 times daily being particularly preferred.


It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of
administration, route of administration, and rate of excretion, drug combination (i.e., other drugs being administered to the patient), the severity of the particular disease undergoing therapy, and other factors, including the judgment of the
prescribing medical practitioner.


Preferred compounds of the invention will have favorable pharmacological properties.  Such properties include, but are not limited to bioavailability (e.g., oral bioavailibilty, preferably high enough to permit oral administration of doses of
less than 2 grams, preferably of less than or equal to one gram), low toxicity, low serum protein binding and desirable in vitro and in vivo half-lifes.  Distribution in the body to sites of complement activity is also desirable, e.g., compounds used to
treat CNS disorders will preferably penetrate the blood brain barrier, while low brain levels of compounds used to treat periphereal disorders are typically preferred.


Assays may be used to predict these desirable pharmacological properties.  Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers.  Toxicity to cultured hepatocyctes may
be used to predict compound toxicity.  Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.


Serum protein binding may be predicted from albumin binding assays.  Such assays are described in a review by Oravcova, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27).


Compound half-life is inversely proportional to the frequency of dosage required for the effective administration of a compound.  In vivo half-lifes of compounds may be predicted, e.g., from assays of microsomal half-life as described by Kuhnz
and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).


Preparation of Compounds


Representative methods for preparing the compounds of the invention are shown in the following Schemes.  Schemes 1 and 2 show the preparation of arylimidazole compounds.  Scheme 1 illustrates the preparation of arylimidazole compounds where
R.sub.1 is hydrogen or halogen.  Scheme 2 represents of the preparation of aryl imidazole compounds where R.sub.1 is alkyl.  Within Schemes 1 and 2 the variables Ar.sub.1 , Ar.sub.2, R.sub.1 , R.sub.2, R.sub.3 and R.sub.4.about.are defined as above for
Formula I. ##STR232##


As shown in Scheme 1, an appropriately substituted arylnitrile 10 is converted to the imidate 11 via treatment with hydrogen chloride gas in methanol followed by subsequent treatment with base to release the free base.  Amidine 12 is prepared
from 11 by treatment with a primary amine.  2-Arylimidazole-4-carboxaldehyde 13 is prepared from 12 by one of several methods described in the chemical literature, for instance, by treatment with 2-bromo-3-isopropoxyacrolein in the presence of base. 
See, for example, J. Org, Chem., 62: 8449 (Shilcrat et al., 1997).


Aldehyde 13 can then be transformed into hydroxymethylimidazole 14 either by reduction (for cases where R.sub.4 is hydrogen) or by treatment with the appropriate organometallic (for cases where R.sub.4 is C1-C6 alkyl).  The hydroxy group of 14 is
converted to either a halogen or sulfonate ester leaving group.  Treatment of this intermediate with an appropriate secondary amine in the presence of base provides 2-aryl-4-aminomethylimidazole 15.  Alternatively, the aminoalkyl functionality of 15 may
be elaborated by sequential amination-acylation-reduction steps.  In situations where R.sub.1 is a halogen, it may be prepared from 15 (R.sub.1 =H) by treatment with the molecular halogen, a halosuccinimide or the like.


As shown in Scheme 2, an appropriately substituted 2-aryl-4-substitutedimidazole 20 can be N-alkylated by treatment with base such as sodium hydride and an alkyl halide or alkylsulfonate ester to provide the trisubstituted imidazole 21. 
Hydroxymethylation of 21 under the conditions of the Mannich reaction provides hydroxymethylimidazole 22.  In examples where R.sub.3 is alkyl, hydroxymethyl derivative 24 is prepared from 22 by oxidation to aldehyde 23 and subsequent treatment with an
appropriate organometallic reagent such as an alkyl lithium or Grignard reagent.  Conversion of 22 or 24 to the desired 2-aryl-5-aminomethylimidazoles is carried out by conversion of the hydroxymethyl to a halogen or sulfonate ester leaving group
followed by treatment with a secondary amine.  Alternatively, the aminoalkyl functionality of the 2-aryl-5-aminomethylimidazole product may be elaborated by sequential amination-acylation-reduction steps.  ##STR233##


The 2-aryl-4-substitutedimidazole 20 may be prepared by methods de scribed in the chemical literature, for instance, via condensation of an arylamidine with a halomethyl or hydroxymethyl ketone.


Cycloalkylimidazoles


An illustration of the preparation of compounds of the Cycloalkylimidazole compounds of the present invention is given in Scheme 3.  Within Scheme 3 the variables n, Ar.sub.1 , Ar.sub.2, R.sub.2, R.sub.3, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.5a, R.sub.6a, R.sub.7 and X are defined previously.  ##STR234##


As shown in Scheme 3, an appropriately substituted arylamidine 30 is condensed with an appropriately substituted 2-halo-3-alkoxyenone 31 to provide a 2-aryl-4,5-cycloalkylimidazole 32.  The ketone functionality of 32 can be either reduced
(R.sub.7 =H) or treated with an appropriate organometallic (for cases where R.sub.7 is alkyl) to give the cyclic alcohol 33.  Compounds of general formula 34 can be prepared from 33 by one of several methods described in the chemical literature, for
instance, by treatment with thionyl chloride or by treatment with an alkyl or arylsulphonyl chloride in the presence of base.


Compounds of formula 34 can then be transformed into compounds of general Formula 35 by direct treatment with the appropriate secondary amine.  Alternatively, the X functionality of 34 may be transformed into a tertiary amine in a stepwise
manner.  In this case, 34 would be treated with a primary amine to provide an intermediate secondary amine.  This, in turn, could be alkylated to give cycloalkylimidazole compounds of the invention.


Pyridines


An illustration of the preparation of pyridine compounds of the present invention is given in Scheme 4.  Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds
encompassed by the present invention.  Within Scheme 4 the variables Ar.sub.1, Ar.sub.2, R, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are defined as previously described.  ##STR235##


As shown in Scheme 4, an appropriately substituted 4-phenyloxazole 40 is condensed with an appropriately substituted maleic acid to provide a 2-phenylisonicotinic acid 41.  The carboxylic acid functionality of 41 can be reduced directly to the
primary alcohol (43, R.sub.3 =H) or converted by methods known to the art to an intermediate aldehyde 42 and subsequently treated with the appropriate organometallic (for cases where R.sub.3 is alkyl) to give a secondary alcohol 43.  Compounds of general
formula 44 can be prepared from 43 by one of several methods described in the chemical literature, for instance, by initial treatment with thionyl chloride or with an alkyl or arylsulphonyl chloride in the presence of base, followed by subsequent
condensation with a primary amine.  Compounds of formula 44 can then be transformed into compounds of formula 45 by direct treatment with the appropriate alkylating agent or, alternatively, by reductive alkylation.  Alternatively, the tertiary amine
functionality of formula 45 may be realized directly from compounds of formula 43 by initial treatment with thionyl chloride or with an alkyl or arylsulphonyl chloride in the presence of base, followed by subsequent condensation with a secondary amine.


Pyrazoles


An illustration of the preparation of arylpyrazole compounds of the present invention is given in Scheme 5.  Within Scheme 5 the variables Ar.sub.1 , Ar.sub.2, R.sub.1 , R.sub.2, R.sub.3, and R.sub.4 are defined as previously described. 
##STR236##


As shown in Scheme 5, an appropriately substituted phenylhydrazine adduct 50 is condensed with an appropriately substituted .alpha.-ketoester 51, in the presence of a Lewis acid, preferably ZnCl.sub.2, with heating at 50-200.degree.  C.,
preferably at 125.degree.  C. to provide a 1-phenylpyrazole ester 52.  The carboxylic acid functionality of 52 can be reduced directly to the primary alcohol (53, R.sub.3 =H) or converted by methods known to the art to an intermediate aldehyde and
subsequently treated with the appropriate the appropriate organometallic (for cases where R.sub.3 is alkyl) to give a secondary alcohol 53.  Compounds of general formula 54, where LG represents a leaving group, can be prepared from 53 by one of several
methods described in the chemical literature, for instance, by initial treatment with thionyl chloride or with an alkyl or arylsulphonyl chloride in the presence of base, followed by subsequent condensation with a primary amine.  Compounds of formula 54
can then be transformed into compounds of formula 58 by sequential treatment with the appropriate primary amine followed by direct alkylation or reductive alkylation of the intermediate secondary amine.  Alternatively, the tertiary amine functionality of
formula 58 may be realized directly from compounds of formula 53 by initial treatment with thionyl chloride or with an alkyl or arylsulphonyl chloride in the presence of base, followed by subsequent condensation with a secondary amine.


An alternative route to the preparation of compounds of Formula 58 from the 1-phenylpyrazole ester 52 may be realized by hydrolysis of 52 to a carboxylic acid of general structure 56, followed by amide formation to provide 57 and, finally,
reduction of the amide functionality to the tertiary amine of 58 (R.sub.3 =H).


Scheme 6.  Preparation of 2-(1-aryl-1,2,3,4-Tetrahydroiso Quinolin-2-yl) Acetamides and Bicyclics of Other Ring Sizes (n=0, 1, 2, 3.  etc) ##STR237##


The 2-(1,2,3,4-tetrahydroisoquinolin-2-yl) acetamides of general formula 62 of the present invention may be prepared according to the procedure described graphically in Scheme 6, wherein a compound of general Formula 60, prepared according to
literature procedures, (for example: Scully, Frank E., Jr.; Schlager, John J. Synthesis of dihydroisoquinolines and 1-substituted tetrahydroisoquinolines.  Heterocycles (1982), 19(4), 653-6 or Shinohara, Tatsumi; Takeda, Akira; Toda, Jun; Terasawa,
Noriyo; Sano, Takehiro.  A highly efficient synthesis of 1-methyl-1-benzyl-, and 1-phenyl-1,2,3,4-tetrahydroisoquinolines by a modified Pummerer reaction.  Heterocycles (1997), 46: 555-566.) is combined (in an appropiate solvent in the presence of an
organic or inorganic base) with an appropriately substituted acetamide derivative possessing a leaving group X at its 2 position.  For example, X may be halogen, alkyl or aryl sulfonate, or polyfluoroalkylsulfonate.  Acetamides of general Formula 61 may
be prepared via condensation of the appropriate secondary amine with a 2-haloacetylhalide (such as 2-chloroacaetyl chloride) in the presence of base.  Alternatively acetamides of general formula 61 can be prepared by condensation of the appropriate
secondary amine with either a 2-(alkylsulfonylester)acetic acid or 2-(arylsulfonylester)acetic acid in the pressence of an coupling agent such as CDI or the like.


Within Scheme 6, R.sub.1 , R.sub.2, R.sub.3, R.sub.4 and R.sub.5 may be the same or different and are chosen from hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, trifluoromethyl, trifluoromethoxyl, cyano, nitro,
hydroxy carbonyl (COOH), aminocarbonyl (CONH.sub.2), mono or dialkylamihocarbonyl, sulfonamido, mono or dialkylsulfonamido, amino, mono- or di-alkylamino, aceto, acetoxy or 3,4-methylenedioxy or ethylenedioxy.  The term n refers to an integer from 1 to
3.  R.sub.6 may be C.sub.1 -C.sub.9 straight or branched chain alkyl, benzyl (substituted or unsubstituted), phenylethyl (substituted or unsubstituted), phenylpropyl (substituted or unsubstituted), or may be cycloalkyl fused with an aromatic group such
as 1,2,3,4-tetrahydronaphthyl, 1- or 2-indanyl or suberanyl.  ##STR238##


The preparation of the ortho biarylamides of the present invention may be carried out via a series of chemical transformations similar to those displayed graphically in Scheme 7.  An individual skilled in the art may find modifications of one or
several of the synthetic steps described herein without diverting significantly from the overall synthetic scheme.


Thus, as shown, the synthetic route begins with a benzoic acid of general structure 70 possessing a group X at the ortho position.  This X group may be iodine, bromine, chlorine, sulfonate ester or polyfluoroalkylsulfonate ester.  The benzoic
acid may also be substituted by up to four independently chosen substitutents represented by the variables R.sub.1 -R.sub.4.  Examples of suitable substituents include hydrogen, chlorine, fluorine, cyano, C.sub.1 -C.sub.6 straight or branched chain
alkyl, C.sub.1 -C.sub.6 straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy, nitro, amino, mono or dialkyl amino, sulfonamido, mono or dialkylsulfonamido, alkylthio e.g. methylthio, alkylsulfoxide, alkylsulfone, acetyl, acetoxy,
alkoxycarbonyl (COOAlkyl) or dialkylaminocarbonyl (CON[alkyl].sub.2).  Additionally, two adjacent groups (i.e R.sub.1 and R.sub.2, or R.sub.2 and R.sub.3 or R.sub.3 and R.sub.4) may be taken together with a chain of from 3 to 5 methylene carbons to form
a alkyl ring of from five to seven carbons fused to the benzoic acid moiety.  Additionally, two adjacent groups (i.e R.sub.1 and R.sub.2, or R.sub.2 and R.sub.3 or R.sub.3 and R.sub.4) may be taken together with an alkyloxy chain, for example OCH.sub.2 O
or OCH.sub.2 CH.sub.2 O to form an oxygen-containing moiety (in this example methylenedioxy or ethylenedioxy, respectively) fused to the benzoic acid.


This benzoic acid is then activated by conversion to an acid chloride with thionyl chloride, oxalyl chloride or the like.  Alternatively, it may be activated by treatment with carbonyldiimidazole or a similar agent.  The activated benzoic acid is
then treated with an appropriate secondary amine in the presence of base to provide a tertiary amide of general structure 71.


Amide 71 is then converted to the biaryl structure 72 through the use of aryl coupling reactions know in the chemical literature.  Examples of such reactions are the Stille reaction where an aryl trialkyltin reagent is coupled to an appropriate
aryl in the presence of a catalyst such as palladium or nickel; or a Suzuki reaction where a arylboronic acid is coupled to an appropriate aryl in the presence of a nickel or palladium catalyst in the presence of base.


The group "Ar" of General structure 72 may be a phenyl which may be substituted with up to five additional independently chosen substitutents, e.g. hydrogen, halogen, cyano, C.sub.1 -C.sub.6 straight or branched chain alkyl, C.sub.1 -C.sub.6
straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy, nitro, amino, mono or dialkyl amino, sulfonamido, mono or dialkylsulfonamido, alkylthio e.g. methylthio, alkylsulfoxide, alkylsulfone, acetyl, acetoxy, hydroxycarbonyl (COOH),
alkoxycarbonyl (COOAlkyl), aminocarbonyl (CONH.sub.2), monoalkylaminocarbonyl, dialkylaminocarbonyl (CON[akyl].sub.2, methylenedioxy or ethylenedioxy.


The Ar of General Structure 72 may also represent a heteroaryl group such as 1- or 2-thienyl or 1- or 2-furanyl.  Such a heteroaryl group which may be additionally substituted by up to three independently chosen substituents, such as hydrogen,
halogen, cyano, C.sub.1 -C.sub.6 straight or branched chain alkyl, C.sub.1 -C.sub.6 straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy, dialkyl amino, sulfonamido, mono or dialkylsulfonamido, alkylthio e.g. methylthio, alkylsulfoxide,
alkylsulfone, acetyl, acetoxy, hydroxycarbonyl (COOH), alkoxycarbonyl (COOAlkyl), aminocarbonyl (CONH.sub.2), monoalkylcarbonyl, dialkylaminocarbonyl (CON[alkyl].sub.2.  ##STR239##


The preparation of 2-imidazolyl, 2-pyrrazolyl and 2-(1,2,4)-triazolyl benzamides begins with an appropriately substituted benzonitrile derivative having a leaving group X at the position ortho to the carboxylic acid functionality.  Most commonly
this group would be a fluorine or chlorine group.  This benzonitrile may be optionally substituted or additionally substituted by up to four substituents (R.sub.1 -R.sub.4) which may be the same or different (examples of such substituents are: hydrogen,
halogen,.  cyano, C.sub.1 -C.sub.6 straight or branched chain alkyl, C.sub.1 -C.sub.6 straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy, nitro, amino, mono or dialkyl amino, sulfonamido, mono or dialkylsulfonamido, methylthio,
alkylsulfoxide, alkylsulfone, acetyl, acetoxy, alkoxycarbonyl (COOAlkyl) or dialkylaminocarbonyl (CON[alkyl].sub.2).


The benzonitrile 73 is mixed with the azaheterocycle 74 (wherein A and B may be either nitrogen or carbon with the caveat that both A and B not be carbon.  R.sub.5 and R.sub.6 may be the same as those groups described for R.sub.1 -R.sub.4.) This
condensation may be carried out either in a single phase system in an appropriate solvent and base, or in a two-phase manner using a phase transfer catalyst.  2-Azaheterocyclicbenzonitrile 75 is the hydrolyzed to the corresponding benzoic acid 76 via
means common to the chemical literature,.for instance mineral acid.


The benzoic acid 76 is then activated via thionyl chloride, CDI or other means known to the chemical literature and condensed with an appropriately substituted secondary amine toprovide the desired final products 77.


EXAMPLES


The general methods given in Schemes 1 to 8 above for the preparation of compounds of the present invention are further illustrated by the following examples.  Specifically, the methods given in Schemes 1 and 2 for the preparation of aryl
imidazoles are illustrated by Examples 1-4, shown below.  An example of the method shown in Scheme 3 for the preparation of cycloalkylimidazoles is given in example 5, and example of the method shown in Scheme 4 for the preparation of arylpyridines is
given in example 6, and an example of the method shown in Scheme 5 for the preparation of arylpyrazoles is given in example 7.  The method shown by Scheme 6 for the preparations of 2-(1-Aryl-1,2,3,4-tetrahydroisoquinolin-2-yl)acetamides is further
illustrated in example 8.  The methods shown in Schemes 7 and 8 for the preparation of ortho biarylamides and azaarylamides, respectively, are exemplified in Examples 9 and 10.  Unless otherwise specified all starting materials and reagents are of
standard commercial grade, and are used without further purification, or are readily prepared.  from such materials by routine methods.  Those skilled in the art of organic synthesis will recognize that starting materials and reaction conditions may be
varied to achieve the desired end product.


Example 1


Preparation of an Arylimidazole Compound: 1-(1-Butyl)-2-phenyl-5-N,N-di[3,4-methylenedioxyphenylmethyl])aminomethyli midazole (Compound 106)


N-(n-butyl)-benzamidine (101).  To a solution of methyl benzimidate hydrochloride (12 g, 0.07 mole) in dimethylformamide (DMF, 20 mL) is added 7 ml of triethylamine at 0.degree.  C. After 2 h the reaction is filtered to remove triethylamine
hydrochloride.  To the filtrate is added 3.68 g of 1-butylamine and the mixture is heated to 60.degree.  C. for 6 h. After cooling the mixture is partitioned between ethyl acetate and water.  The organic layer is washed with brine, dried over sodium
sulfate and concentrated to provide 13.28 g of the amidine as a yellow oil.  .sup.1 H NMR (400 MHz, CDCl.sub.3) .delta.  7.55 (m, 2H), 7.4 (m, 3H), 3.37 (bm, 2H), 1.62 (m, 2H), 1.42 (m, 2H), 0.95 (t, J=7 Hz, 3H).


1-(1-Butyl)-2-phenylimidazole-5-carboxaldehyde (102).  To a solution of 101 (13.28 g) and 2-bromo-3-isopropoxyacrolein (22 g) in chloroform (150 ml) is added potassium carbonate (15.5 g) and water (19 ml).  The mixture is stirred at room
temperature overnight.  The aqueous layer is discarded and the organic layer is washed with water (3.times.100 mL), dried (Na.sub.2 SO.sub.4) and concentrated.  The residue is purified via flash chromatography (5% MeOH/CHCl.sub.3) to provide the desired
imidazole carboxaldehyde as a pale yellow oil (21.55 g).  .sup.1 H NMR (400 MHz, CDCl.sub.3) .delta.  9.75 (s, 1H), 7.90 (s, 1H), 7.55 (m, 2H), 7.45 (m, 3H), 4.38 (t, J=8Hz, 2H), 1.75 (m, 2H), 1.22 (m, 2H), 0.91 (t, J=7 Hz, 3H).


Representative Preparation of a 1-Alkyl-2-aryl-4-aminomethylimidazole: 1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methylendioxyphenylmethyl])aminomethyli midazole) ##STR240##


1-(1-Butyl)-2-phenyl-5-hydroxymethylimidazole (103).  Aldehyde 102 is dissolved in methanol (150 mL).  Sodium borohydride (3 g) is added in portions.  After the addition was complete, the reaction is diluted with water and concentrated.  The
residue is dissolved in ethyl acetate, washed with brine, dried (Na.sub.2 SO.sub.4) and concentrated.  The product is purified by flash chromatography on silica gel (5% MeOH/CHCl.sub.3) to give 4.17 g of 103 as a cream colored solid.  .sup.1 H-NMR (400
MHz, CDCl.sub.3): .delta.  0.79 (3H, t, d=7.4), 1.18 (2H, m, d=7.4), 1.60 (2H, m, d=7.6), 4.03 (2H, dd, d=7.6), 4.56 (2H, s), 6.84 (1H, s), 7.39-7.50 (3H, m),7.50-7.53 (2H, m).


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl])aminomethylimida zole (104).  Hydroxymethylimidazole 103 (0.82 g) is dissolved in chloroform (10 ml) and treated with thionyl chloride (1 ml).  The solution is heated to 50.degree.  C.
for 30 min, cooled and evaporated.  The residue is washed with benzene and evaporated to give the intermediate chloromethyl hydrochloride as a white powder which is taken up in acetonitrile (30 mL).  This is added dropwise to a solution of piperonylamine
(5 ml) in acetonitrile (10 mL).  The reaction is allowed to stand overnight and then evaporated.  The residue is taken up in ethyl acetate and washed with water.  The organic layer is dried (Na.sub.2 SO.sub.4) and concentrated.  Purification on silica
gel (10% MeOH/CHCl.sub.3) provides the product as a pale yellow oil (0.91 g).  .sup.1 H NMR (400 MHz, CDCl.sub.3): .delta.  0.79 (3H, t, d=7.4), 1.18 (2H, m, d=7.4), 1.56 (2H, m, d=7.4), 3.75 (4H, s), 4.04 (2H, dd, d=8), 5.92 (2H, s), 6.76 (2H, m), 6.84
(1H,s), 6.97 (1H, s), 7.38-7.44 (3H, m), 7.53-7.56 (2H, m).


1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl methyl]-N-(3,4-methylenedioxyphenylcarboxyl)aminomethylimidazole (105).  Compound 104 (160 mg, 0.44 mmol) is dissolved in chloroform (5 ml, pentene stabilized) and treated sequentially with
piperonyloyl chloride (100 mg) and triethylamine (1 ml).  The mixture is stirred at room temperature overnight.  The solution is concentrated and the residue taken up in ethyl acetate.  The organic is washed with water, dried (Na.sub.2 SO.sub.4) and
concentrated.  Purification by preparative thin layer chromatography (5% MeOH/CHCl.sub.3) provides compound 105 as a pale yellow oil (240 mg).  .sup.1 H-NMR (400 MHz, CDCl.sub.3): .delta.  0.75 (3H, br), 1.16 (2H, br), 1.49 (2H, br), 4.01 (2H, br), 4.54
(2H, br), 4.68 (2H, br), 5.97 (2H, s), 5.99 (2H, s), 6.66 (2H, d, d=7.2), 6.80 (2H, t, d=8), 6.98-7.02 (2H, m), 7.40-7.47 (3H, m), 7.56 (2H, d, d=6.8).


1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxy phenylmethyl])-aminomethylimidazole (106).  Amide 105 (215 mg) in tetrahydrofuran (THF, 3 ml) is added dropwise to a solution of alane (1 M in THF, 2 ml) and the resulting solution is stirred for
2.5 h at room temperature.  A solution of sodium hydroxide (15% NaOH, 1 ml) is added and the mixture is extracted with chloroform.  The organic extracts are dried (Na.sub.2 SO.sub.4) and concentrated.  Purification by preparative thin layer
chromatography (10% MeOH/CHCl.sub.3) provided compound 106 as a colorless oil (115 mg).  .sup.1 H-NMR (400 MHz, CDCl.sub.3): .delta.  0.70 (3H, t, d=7.6), 0.98 (2H, m, d=7.6), 1.30 (2H, m), 3.44 (4H, s), 3.52 (2H, s), 3.98 (2H, dd, d=8), 5.92 (4H, s),
6.74 (4H, s), 6.69 (2H, s), 7.02 (1H, s), 7.36-7.42 (3H, m), 7.54 (2H, dd, d=1.4, 6.6).  The hydrochloride salt (m.p.  187-190.degree.  C.) was prepared in isopropanol.


Example 2


Preparation of 1-(1-Butyl)-2-phenyl-5-(1-[N-{3,4-methylenedioxyphenylmethyl]}-N-phenylmet hyl]amino)ethylimidazole (Compound 108)


1-Butyl-2-phenyl-5-(1-hydroxyethyl)imidazole (107).  A solution of aldehyde 102 (230 mg) in diethyl ether (30 mL) is placed in a separatory funnel and treated with a solution of


Preparation of 1-(1-Butyl)-2-phenyl-5-(1-[N-[{3,4-methylendioxyphenylmethyl]}-N-[phenylme thyl]aminoethylimidazole)


##STR241##


methyl lithium (1.4 M in THF, 1.5 ml).  After 10 min, the solution is washed with ammonium chloride solution (1 M, 20 ml), dried (Na.sub.2 SO.sub.4) and concentrated.  The resulting dark oil is purified by preparative TLC (10% MeOH/CHCl.sub.3) to
provide compound 107 as a colorless oil (180 mg).  .sup.1 H NMR (400 MHz, CDCl.sub.3) .delta.  7.56 (d, J=2 Hz, 2H), 7.4 (m, 3H), 7.01 (s, 1H), 4.86 (q, J=7 Hz, 1H), 4.18 (m, 1H), 4.0 (m, 1H), 1.63 (d, J=6.6 Hz, 3H), 1.63 (m, 2H), 1.23 (m, 2H), 0.81 (t,
J=7 Hz, 3H).


1-Butyl-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]-N-phenylmethyl)aminoethyli midazole (108).  A solution of compound 107 (80 mg) in chloroform (10 ml) is treated with thionyl chloride (1 ml) and heated to 50.degree.  C. for 30 min. The solution is
then concentrated, diluted with chloroform and reconcentrated to provide the intermediate chloromethyl hydrochloride as an oil.  This material is taken up in chloroform (5 ml) and treated sequentially with N-benzylpiperonylamine (80 mg) and
triethylamine.  After stirring overnight, the reaction is washed with saturated potassium carbonate solution, dried (Na.sub.2 SO.sub.4) and concentrated.  Purification by preparative thin layer chromatography (10% MeOH/CHCl.sub.3) provides compound 108
as a colorless oil (62 mg).  .sup.1 H NMR (400 MHz, CDCl.sub.3) .delta.  7.46-7.43 (m, 1H), 7.2-7.3 (m, 9H), 6.74-6.86 (m, 4H), 5.94 (s, 2H), 4.82 (q, J=6.8 Hz, 1H), 4.33 (m, 2H), 3.78 (s, 2H), 3.53 (s, 2H), 1.83 (d, J=6.8 Hz, 3H), 1.62-1.68 (m, 2H),
1.21 (q, J=7.8 Hz, 2H), 0.82 (t, J=7.8 Hz, 3H).


Example 3


Preparation of 1-Butyl-2-phenyl-4-bromo-5-(N-phenylmethyl-N-11-butyl]amino-methylimidazol e (Compound 110)


Preparation of 1-(1-Butyl)-2-phenyl-4-bromo-5-[N-phenylmethyl-N-[1-butyl])aminomethylimid azole)


##STR242##


1-Butyl-2-phenyl-5-(N-benzyl-N-butyl)aminomethylimidazole (109).  A solution of compound 102 (115 mg) and N-butylbenzylamine (85 mg) in toluene (10 ml) is allowed to stand overnight.  Treatment of the reaction with sodium borohydride (100 mg) and
ethanol (2 mL) followed by aqueous workup and purification on silica gel (10% MeOH/CHCl.sub.3) provides compound 109 as a colorless oil (35 mg).  .sup.1 H NMR (400 MHz, CDCl.sub.3) .delta.  7.2-7.5 (m, 10H), 6.98 (s, 1H), 4.0 (t, J=8 Hz, 2H), 3.55 (s,
2H), 3.52 (s, 2H), 2.42 (t, J=8 Hz, 2H), 1.2-1.55 (m, 6H), 1.05 (m, 2H), 0.84 (t, J=7 Hz, 3H), 0.72 (t, J=7 Hz, 3H).


1-Butyl-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[1-butyl])aminomethylimidazole (110).  To a solution of 109 (30 mg) in acetonitrile (4 mL) was added N-bromosuccinimide (16 mg).  The resulting mixture was heated to 60.degree.  C. and the progress of
the reaction followed by TLC.  The cooled reaction mixture was diluted with ethyl acetate and washed twice with water.  Purification by preparative thin layer chromatography (10% MeOH/CHCl.sub.3) provided compound 110 as a colorless oil (22 mg).  .sup.1
H NMR (400 MHz, CDCl.sub.3) .delta.  7.2-7.5 (m, 10H), 3.98 (t, J=8 Hz, 2H), 3.55 (s, 2H), 3.53 (s, 2H), 2.46 (t, J=7 Hz, 2H), 1.52 (m, 2H), 1.3 (m, 4H), 0.98 (q, J=7 Hz, 2H), 0.84 (t, J=7 Hz, 3H), 0.70 (t, J=7 Hz, 3H).


Example 4


Preparation of 1-(1-Butyl)-2-phenyl-4-methyl-5-(N-[3,4-methylenedioxyphenyl-methyl]-N-phe nylmethyl)aminomethylimidazole.  (Compound 114)


1-Butyl-2-phenyl-4-methylimidazole (112).  To a solution of 4-methyl-2-phenylimidazole (111, 15.8 g) in dimethylformamide (100 ml) is added sodium hydride.  (4.4 g, 60% in mineral oil) in small portions.  After the addition is complete, the
mixture was stirred for an additional 20 min and treated with 1-iodobutane (18.8 g).  The reaction is fitted with a reflux condensor and heated at 100.degree.  C. for 12 h. The cooled reaction mixture is partitioned between water (300 ml) and diethyl
ether (300 ml).  The organic layer is washed with water (3.times.200 ml), dried (Na.sub.2 SO.sub.4) and concentrated to provide 20.5 g of N-butylimidazoles.  Analysis by .sup.1 H-NMR and GC-MS revealed mixture of 1-butyl-2-phenyl-4-methylimidazole (112)
and 1-butyl-2-phenyl-5-methylimidazole in a ratio of 11.5/1.  The mixture was carried on to the next step without purification.


1-Butyl-2-phenyl-4-methyl-5-hydroxymethylimidazole (113).  A solution of 112 (1 g) in acetic acid (10 mL) and 40% aqueous formaldehyde (2 mL) is refluxed for 14 h. The reaction is then concentrated and dried by repeated reconcentration with
toluene.  The residue is purified by column chromatography (10% MeOH/CHCl.sub.3).  The fractions are assayed by GC and those fractions uncontaminated by the isomeric hydroxymethylimidazole combined.  Concentration of the combined.  fractions provides
compound 113 (320 mg) as a pale yellow oil.  .sup.1 H NMR (400 MHz, CDCl.sub.3) .delta.  7.4-7.6 (m, 6H), 4.61 (s, 2H, CH.sub.2 OH), 4.02 (t, J=7 Hz, 2H, NCH.sub.2), 2.22 (s, 3H, Me), 1.63 (m, 2H, 1.25 (m, 2H), 0.81 (t, J=7 Hz, 3H).


Preparation of 1(1-Butyl)-2-phenyl-4-methyl-5-(N-[3,4-methylenedioxyphenyl]-N-phenylmethy l)aminomethylimidazole


##STR243##


1-Butyl-2-phenyl-4-methyl-5-(N-benzyl-N-butyl)aminomethylimidazole (114).  Compound 114 (23 mg) is prepared from 113 (50 mg) in a, method similar to that used to obtain compound 108.  .sup.1 H NMR (400 MHz, CDCl.sub.3) .delta.  7.5-7.55 (m,2H),
7.38-7.42 (m, 3H), 7.23-7.30 (m, 5H), 3.95 (t, J=7.5 Hz, 2H), 3.55 (s, 2H), 3.53 (s, 2H), 2.40 (t, J=7 Hz, 2H), 2.22 (s, 3H), 1.25-1.40 (m, 6H), 1.05 (m, 2H), 0.82 (t, J=7 Hz, 3H).  0.70 (t, J=7 Hz, 3H); MS (LCMS) m/e 390 (M.sup.+ +1).


Example 5


Preparation of a Cyloalkylimidazole Compound: 4-{Butyl(1-butyl-2-phenyl(4,5,6-trihydrocyclopenta[3,2-d]imidazol-6-yl])am ino]methyl}-3-chlorophenol


N-(n-butyl)-benzamidine (120).  To a solution of methyl benzimidate hydrochloride (12 g, 0.07 mole) in dimethylformamide (DMF, 20 mL) is added 7 ml of triethylamine at 0.degree.  C. After 2 h the reaction is filtered to remove triethylamine
hydrochloride.  To the filtrate is added 3.68 g of 1-butylamine and the mixture is heated to 60.degree.  C. for 6 h. After cooling the mixture is partitioned between ethyl acetate and water.  The organic layer is washed with brine, dried over sodium
sulfate and concentrated to provide 13.28 g of the amidine as a yellow oil.  .sup.1 H NMR (CDCl.sub.3) 7.55 (m, 2H), 7.4 (m, 3H), 3.37 (bm, 2H), 1.62 (m, 2H), 1.42 (m, 2H), 0.95 (t, J=7 Hz, 3H).


2-Bromo-3-methoxycyclopentenone (131) is prepared via the method of Curran et al JACS, vol 112, page 5601.  To a suspension of 1,3-cyclopentanedione (10 g) in chloroform (700 ml) is added a N-bromosuccinimide (18.2 g).  The mixture is refluxed
for 2 h, cooled and concentrated.  Methanol (700 mL) and p-toluenesulfonic acid (1 g) are added and the solution is refluxed overnight.  The mixture is concentrated to 100 ml, diluted with methylene chloride (500 mL) and poured into water.  The aqueous
layer is discarded and the organic layer is washed with water (3.times.100 mL), dried (Na.sub.2 SO.sub.4).  and concentrated.  The residue is crystallized from ethyl acetate to give 131 as tan crystals (1.67 g).


1-Butyl-2-phenyl-4,5-dihydrocyclopenty[1,2-d]imidazol-6-one (Compound 132).  To a mixture of amidine 130 (3.52 g, 20 mmol) and enone 13 (4.58 g, 24 mmol) in chloroform (40 mL) and water (5 mL) was added solid potassium carbonate (3.32 g, 24
mmol).  The resulting mixture is refluxed overnight.  After cooling, the mixture is washed with water, dried (Na.sub.2 SO.sub.4) and concentrated.  Purification on silica gel eluting with 25% ethyl acetate/hexane gives the desired product 132 (3.0 g)
LC-MS (M++1): 255.  .sup.1 H-NMR (.delta., CDCl.sub.3): 0.84 (t, J=7.6 Hz, 3H), 1.23 (dt, J=7.0, 7.6 Hz, 2H), 1.81 (m, 2H), 2.95 (m, 4H), 4.13 (t, J=7.6 Hz, 2H) 7.5-7.45 (m, 3H), 7.76-7.6 (m, 2H) ppm.


1-Butyl-2-phenyl-4,5-dihydrocyclopenty[1,2-d]imidazol-6-ol (Compound 133).  To a solution of 132 (2.68 g) in methanol (20 mL) is added sodium borohydride (1.5 equiv) and the mixture stirred overnight.  The mixture is concentrated, diluted with
chloroform and washed with 0.5 N NH.sub.4 Cl solution.  The organic layer is dried (Na.sub.2 SO.sub.4) and concentrated to provide the desired product 133.  LC-MS (M+1) 257.


Butyl(1-butyl-2-phenyl-4,5,6-trihydrocyclopentyl[3,2-d]imidazol-6-yl))amine (Compound 135).  Compound 133 (2 g) is dissolved in chloroform (20 mL) and thionyl chloride (5 mL) and the resulting solution is stirred at room temperature overnight. 
The solvent and excess thionyl chloride are evaporated and the crude chloride 134 was dissolved in n-butylamine (10 mL).  After 2 h, the excess butylamine was evaporated, the residue dissolved in ethyl acetate and the organic solution washed with 5% NaOH
solution and water.  The organic layer was dried and concentrated.  The organic residue is purified by column chromatography on silaica gel eluting with 10% CH.sub.3 OH in CHCl.sub.3 to provide the desired secondary amine 135 in 82% yield.  LC-MS (M+1)
312 .sup.1 H-NMR (chemical shift, CDCl.sub.3): 0.83 (t, J=7.2 Hz, 3H), 0.9 (t, J 7.2 Hz, 3H), 1.23 (q, J=7.2 Hz, 2H), 1.35 (q, J=7.2 Hz, 214), 1.46 (m, 2H), 1.70 (m, 2H), 2.24 (m, 1H), 2.55-2.66 (m, 4H), 2.73-2.80 (m, 2H), 3.97-4.04 (m, 2H), 4.30 (d,
J=5.6 Hz, 1H), 7.37-7.44 (m, 3H), 7.55-7.57 (m, 2H).


4-{[Butyl(1-butyl-2-phenyl(4,5,6-trihydrocyclopenta[3,2-d]imidazol-6-yl))am ino]methyl}-3-chlorophenol (Compound 5, Table 1).  To a solution of compound 135 (50 mg) in 1,2-dichloroethane (2 mL) and 2-chloro-4-hydroxybenzaldehyde (30 mg) is added
sodium triacetoxyborohydride (100 mg).  The resulting mixture is allowed to stir overnight.  After washing with 0.5 ammonium chloride solution, the organic layer is dried (Na.sub.2 SO.sub.4) and concentrated.  Purification using preparative thin layer
chromatography eluting with 5% CH.sub.3 OH/CHCl.sub.3 provides the desired product 136 as an oil (21 mg).  LC-MS (M+1) 452, (M-1) 450.  .sup.1 H-NMR (chemical shift, CDCl.sub.3): 0.74 (t, J=7.2 Hz, 3H), 0.83.(t, J=7.2 Hz, 3H), 1.11 (q, J=7.2 Hz, 2H),
1.21-1.33 (m, 2H), 1.41-1.51 (m, 4H), 2.34-2.44 (m, 3H), 2.51-2.57 mL, 1H), 2.60-2.67 (m, 1H), 2.69-2.75 (m, 1H), 3.38 (d, J=7.6 Hz, 1H), 3.47 (d, J=13.6 Hz, 1H), 3.65 (d, J=13.6 Hz, 1H), 3.78-3.96 (m, 1H), 6.62 (dd, J=8,2 Hz, 1H), 6.78 (d, J=2 Hz, 1H),
7.07 (d, J=8 Hz, 1H), 7.35-7.41 (m, 3H), 7.45-7.48 (m, 2H).


Preparation of 4-{[Butyl(1-butyl-2-phenyl(4,5,6-trihydrocyclopenta [3,2-di]imidazol-6yl))amino]methyl}-3-chlorophenol


##STR244##


Example 6


Preparation of 2-phenyl-4-(N,N-di{2H-Benzo[3,4-d]-1,3-dioxolan-5-ylmethyl}amino)methyl-3- butylpyridine


4-Phenyl-5-butyloxazole (140).  A mixture of .alpha.-bromohexanophenone (25.5 g, 0.1 mole), ammonium formate (22 g, 0.35 mole) and formic acid (110 mL) was refluxed with stirring for 3 h. The reaction mixture was poured onto ice and made basic
with 10 N NaOH and extracted with ether.  The organic layer was washed with water, dried over sodium sulfate and concentrated.  The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane.  To provide the
desired compound as an oil (8.3 g, 41 %); .sup.1 H NMR (.delta., CDCl.sub.3, 400 MHz) 7.55 (m, 2H), 7.40 (s, 1H), 7.34 (dd, J=7,7 Hz, 2H), 7.22 (dd, J=7, 7 Hz, 1H), 2.74 (m, 2H), 1.6 (m, 2H), 1.30 (m, 2H), 0.84 (t, J=7 Hz, 3H) ppm.


2-Phenyl-3-butylisonicotinic acid (141).  A mixture of 4-phenyl-5-butyloxazole (12,5 g, 25 mmol) and maleic acid (3.5 g, 30 mmol) is heated at 100.degree.  C. for 30 min. After cooling, the semisolid mass is triturated with ether and the solid
collected by filtration.  .sup.1 H NMR (.delta., CDCl.sub.3, 400 MHz) 11.68 (brs, 1H), 8.72 (d, J=6.0 Hz, 1H), 7.73 (d, J=5.6 Hz, 1H), 7.48-7.51 (m, 2H), 7.42-7.44 (m, 2H), 6.25 (s, 1H), 2.86 (d, J=7.6 Hz, 2H), 1.36 (m, 2H), 1.11 (dt, J=7.6, 7.2 Hz, 2H),
0.68 (t, J=7.6 Hz, 3H).  MS (M+1): 256, (M-1) 254.


2-Phenyl-4hydroxymethyl-3-butylpyridine (142).  4 mL of a 1M solution of lithium aluminum hydride in tetrahydrofuran is added to a solution of 2-phenyl-3-butylisonicotinic acid (13, 510 mg, 2 mmol) in tetrahydrofuran (20 mL).  The reaction is
stirred overnight and then quenched with 5 mL of 15% aqueous NaOH.  The resulting mixture is extracted with ether, dried (Na.sub.2 SO.sub.4) and concentrated to provide the desired hydroxymethylpyridine as an oil (470 mg).  LC-MS (M+1): 242; .sup.1 H NMR
(.delta., CDCl.sub.3) 8.35 (1H, d, J=5.2 Hz), 7.30-7.39 (6H, m), 4.59 (2H, s), 2.43 (2H, t, J=8.0 Hz), 1.23 (2H, m), 1.13 (2H, m), 0.70 (3H, t, J=7.2 Hz).


2-Phenyl-4-(N-{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl})aminomethyl-3-butyl pyridine (143).  Thionyl chloride (200 mg, 1.67 mmol) is added to a solution of 2-phenyl-4-hydroxymethyl-3-butylpyridine (400 mg, 1.66 mmol) in pentene stabilized
chloroform (8 mL) and the mixture is heated to 50.degree.  C. for 2 h. The resulting mixture is cooled, washed with saturated sodium bicarbonate solution, dried (Na.sub.2 SO.sub.4) and concentrated.  The resulting crude chloride is taken up in
dimethylformamide (10 mL).  and added dropwise to a refluxing solution of piperonylamine (1.0 g, 4 equiv) in dimethylformamide (30 mL) containing 3 g of powdered potassium carbonate.  After the addition is complete, the resulting mixture is refluxed for
an additional 3 h, cooled and partitioned between water (200 mL) and ether (100 mL).  The ethereal layer is washed 2 times with water, dried (Na.sub.2 SO.sub.4) and concentrated.  The resulting material is purified by chromatography on silica eluting
with 10% CH.sub.3 OH/CHCl.sub.3 to give the desired secondary amine 15.  LC-MS (M+1): 375.3; .sup.1 H-NMR (.delta., CDCl.sub.3): 0.73 (3H, t, J=7.2 Hz), 1.15 (2H, m J=7.2 Hz), 1.30 (2H, m), 2.58 (2H, t, J=8.0 Hz), 3.79 (2H, s), 3.83 (2H, s), 5.93 (2H,
s), 6.75-6.82 (2H, m), 6.89 (1H, d, J=1.2 Hz), 7.36-7.42 (6H, m), 8.45 (1H, d, J=4.8 Hz) ppm.


2-Phenyl-4-(N-{2H-benzo[3,4d]-1,3-dioxolan-5-ylmethyl})aminomethyl-3-butylp yridine (144).  To a solution of 14 (38 mg) in dichloroethane (5 mL) was added piperonal (30 mg).  The resulting mixture was stirred for 3 h after which time sodium
triacetoxyborohydride (150 mg) is added in one portion and the resulting mixture is stirred overnight.  The reaction mixture was quenched with 10% ammonium hydroxide solution (5 ml).  The organic layer is washed with water and extracted with 1N HCl
solution.  The acidic extract is made basic with 1N NaOH solution and extracted with chloroform.  The organic extract is dried (Na.sub.2 SO.sub.4) and concentrated.  The resulting oil is purified on preparative thin layer chromatography eluting with 10%
CH.sub.3 OH/CHCl.sub.3 to give the desired tertiary amine 144 as an oil (18 mg).  LC-MS (M+1): 509.4; .sup.1 H-NMR (.delta., CDCl.sub.3): 0.71 (3H, t, J=7.2 Hz), 1.10 (2H, m, J=7.2 Hz), 2.60 (2H, t, J=8.0 Hz), 3.48 (4H, s), 3.58 (2H, .s), 5.94 (4H, s),
6.75 (1H, d, J=8.0 Hz),6.80 (1H, dd, J=0.8, 8.0 Hz), 6.91 (1H, d, J=0.8 Hz), 7.36-7.43 (5H, m), 7.56 (1H, d, J=5.2 Hz), 8.47 (1H, d, J=5.2 Hz) ppm.


Preparation of 2-Phenyl-4-(N,N-di{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl})aminomethyl-3- butylpyridine


##STR245##


Example 7


Preparation of an Arylpyrazole: 1,3-Diphenyl-4-(N-{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl}-N-butylamino)m ethyl-5-propylpyrazole


N'-Phenyl-N-phenylhydrazone (150).  Benzaldehyde (9.81 g, 9.25 mmol) is added at 0-5.degree.  C. to a solution of phenyl hydrazine (10 g, 9.25 mmol) in ethanol (100 mL).  A cream colored solid forms and the reaction mixture is allowed to stand
for 2h.  The solid is collected by filtration, washed with ice-cold ethanol and dried under vacuum to provide the desired compound, compound 150 (14.92 g); LC-MS m/z 197.2, .sup.1 H NMR (.delta., CDCl.sub.3, 400 MHz) ppm.


Ethyl 1,3-diphenyl-5-propylpyrazole-4-carboxylate (152).  A mixture of 150 (5 g, 25.5 mmol) and ethyl butyrylacetate (20.2 g, 128 mmol) and a catalytic amount of zinc chloride is heated at 125.degree.  C. under an air atmosphere for 3 h. The
reaction vessel is fitted with a short path distillation head and excess ethyl butyrylacetate iss distilled away under vacuum.  The resulting material is purified by column chromatography on silica eluting with 10% ethyl acetate in hexanes to provide the
desired ester 152 as a yellow oil (6.39 g) which crystallizes upon standing.  Recrystallization from diisopropyl ether provides a white solid.  .sup.1 H NMR (.delta., CDCl.sub.3, 400 MHz) MS (M+1): 335.2.


1,3-Diphenyl-4-hydroxymethyl-5-propylpyrazole (153).  To a solution of ester 153 (670 mg, 2 mmol) in tetrahydrofuran (20 mL) is added 4 mL of a 1M solution of lithium aluminum hydride in tetrahydrofuran.  The reaction is stirred overnight and
then quenched with 5 mL of 15% aqueous NaOH.  The resulting mixture is extracted with ether, dried (Na.sub.2 SO.sub.4) and concentrated to provide the desired hydroxymethylpyrazole as an oil (505 mg).  LC-MS (M+1): 293.3; .sup.1 H NMR (.delta.,
CDCL.sub.3) 7.86 (dd, J=8.4 Hz, 2H), 7.34-7.52 (m, 8H), 4.65 (s, 2H), 2.72 (t, J=8.0 Hz, 2H), 1.52 (m, 2H), 0.87 (t, J=7.6 Hz, 3H).


[(1,3-Diphenyl-5-propylpyrazol-4-yl)methyl]butylamine (154).  To a solution of 18 (289 mg) in pentene stabilized chloroform (8 mL) is added thionyl chloride (1 mL) and the mixture heated to 60.degree.  C. for 2 h. The resulting mixture is cooled,
washed with saturated sodium bicarbonate solution, dried (Na.sub.2 SO.sub.4) and concentrated.  The resulting crude chloride is taken up in dimethylformamide (3 mL) and added dropwise to a solution of butylamine (1.0 g) in dimethylformamide (10 mL)
containing 2 g of powdered potassium carbonate.  After the addition is complete, the resulting mixture is stirred for an additional 3 h and partitioned between water (20 mL) and ether (10 mL).  The ethereal layer is washed 2 times with water, dried
(Na.sub.2 SO.sub.4) and concentrated.  The resulting material is purified by chromatography on silica eluting with 10% CH.sub.3 OH/CHCl.sub.3 to give the desired secondary amine 155 (190 mg).  LC-MS (M+1): 348.3; .sup.1 H-NMR (.delta., CDCl.sub.3): 7.87
(dd, J=8.0, 1.6 Hz, 2H), 7.32-7.48 (m, 8H), 3.77 (s, 2H), 2.70 (m, 4H), 1.48 (m, 4H), 1.34 (m, 2H), 0.91 (t, J=7.6 Hz, 3H), 0.87 (t, J=7.6 Hz, 3H) ppm.


1,3-Diphenyl-4-(N-{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl}-N-butylamino)me thyl-5-propylpyrazole (Compound 155).  To a solution of 154 (35 mg) in dichloroethane (5 mL) is added piperonal (30 mg).  The resulting mixture is stirred for 3 h after
which time sodium triacetoxyborohydride (150 mg) is added in one portion and the resulting mixture is stirred overnight.  The reaction mixture is quenched with 10% ammonium hydroxide solution (5 ml).  The organic layer is washed with water and extracted
with 1HCl solution.  The acidic extract is made basic with 1N NaOH solution and extracted with chloroform.  The organic extract is dried (Na.sub.2 SO.sub.4) and concentrated.  The resulting oil is purified on preparative thin layer chromatography eluting
with 10% CH.sub.3 OH/CHCl.sub.3 to give the desired tertiary amine (Compound 155) as an oil (24 mg).  LC-MS (M+1): 482.5; .sup.1 H-NMR (.delta., CDCl.sub.3): 7.87 (d, J=7.2 Hz, 2H), 7.47 (d, J=4.4 Hz, 4H), 7.33-7.43 (m, 4H), 6.77 (s, 1H), 6.70 (s, 2H),
5.92 (s, 2H), 3.5.6 (s, 2H), 3.42 (s, 2H), 2.74 (t, J=8.0 Hz, 2H), 2.37 (t, J=7.2 Hz, 2H), 1.42 (m, 4H), 1.21 (m, 2H), 0.83 (t, J=7.6 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H) ppm.


Preparation of 1,3-Diphenyl-4-N-{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl}-N-butylamino)me thyl-5-propylpyrazole


##STR246##


Example 8


Synthesis of N-(1-Fluorobenzyl)-N-indan-2-yl-2-(6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahyd roisoquinolin-1-yl]acetamide (162)


A mixture of 6, 7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (160, 153 mg, 0.5 mmol), N-(1-fluorobenzyl)-N-indan-2-yl-2-bromoacetamide (161, 180 mg, 0.5 mmol) and potassium carbonate (500 mg) in acetonitrile is heated at
80.degree.  C. overnight.  After cooling, the mixture is filtered and concentrated.  The resulting residue is purified by column chromatography eluting with 5% methanol in chloroform to provide the title product (162) as a thick oil (215 mg, 78%). 
.sup.1 H NMR (CDCl.sub.3) 6.8-7.3 (m, 14H), 6.60(s, 1H), 6.05 (s, 1H), ##STR247##


Example 9


Preparation of 4Trifluoromethyl-biphenyl-2-carboxylic Acid Benzo[1,3dioxol-5-ylmethyl-benzyl-amide (174)


1,1'-carbonyldiimidazole (175 mg) is added to a solution of 2-iodobenzoic acid (248 mg, 1 mmol)(170) in tetrahydrofuran (THF, 5 ml).  The resulting mixture is stirred overnight at room temperature.  A solution of
N-3,4-methylenedioxybenzyl-N-benzylamine (241 mg, 1 equiv)(171) in THF (2 mL) is added and the resulting solution is stirred for 1 h, quenched with water and extracted with diethyl ether.  The organic extracts are dried (Na.sub.2 SO.sub.4) and
concentrated.  The residual material is taken up in dimethoxyethane (10 mL) and a catalytic amount (20 mg) of tetrakis(triphenylphosphine)palladium(0) is added.  The resulting mixture is stirred under an argon atmosphere for 10 min and solid
4-trifluoromethyl]phenylboronic acid (150 mg) is added in one portion.  A second phase of 1N aqueous Na.sub.2 SO.sub.4 is added and the mixture is warmed to 80.degree.  C. for 6 h under a argon atmosphere.  The solution is cooled, diluted with water and
ethyl acetate and filtered through a pad of celite.  The organic phase is dried over sodium sulfate and concentrated.  Purification on silica eluting with 20% ethyl acetate in hexane provided the desired biphenylamide product (174)(410 mg).  The proton
NMR displays a doubled pattern commonly observed for amides which possess some rotational restriction about the amide nitrogen at room temperature.  The ratio of the rotomers is approximately equal.  .sup.1 H NMR (CDCl3) 3.50 and 3.62 (two doublets, J=X
Hz, 1H), 3.72 and 3.83 (two doublets, J=X Hz, 1H), 4.10 and 4.18 (two doublets, J=X Hz, 1H), 5.09 and 5.16 (two doublets, J=x Hz, 1H), 5.95 (d, J=X Hz, 2H, OCH.sub.2 O), 6.30 (m, 1.5H), 6.46 (d, J=1 Hz, 0.5 Hz), 6.60 and 6.66 (two doublets, J=X Hz, 1H),
6.80 (bd, J=X Hz, 1H), 6.86 (m, 1H), 7.16-7.62 (m, 11H).  ##STR248##


4'-Trifluoromethyl-biphenyl-2-carboxylic Acid Benzo[1,3]dioxol-5-ylmethyl-benzyl-amide


Example 10


Preparation of N-Benzo[1,3]dioxol-5-ylmethyl-N-benzyl-2-pyrazol-1-yl-benzamide


2-Pyrazol-1-yl-benzonitrile.  Compound 177.  A solution of 20 mmol of 2-fluorobezonitrile and 40 mmol of pyrrazole is mixed together in dimethylformaide with 1 equivalent of potassium hydroxide and a catalytic amount of 18-crown-6.  The mixture
is stirred at room temperature overnight, quenched with water and ethyl acetate and extracted with ethyl acetate.  The organic extract is washed repeatedly with 1 N NaOH solution.  The organic layer is then diluted with ether and washed with 1N HCl
solution, dried and concentrated.  1H NMR (CDCl.sub.3) 6.55 (t, J=2 Hz, 1H), 7.42 (M, 1H), 7.65-7.82 m, 4H), 8.15 (d, J=1 Hz, 1H).


2-Pyrazol-1-yl-benzoic acid, Compound 178.  A solution of compound 177 in conc HCl is refluxed overnight, cooled and concentrated.  The product is precipitated by addition of 1 N NaOH until pH of 5-6, filtered and dried.  1H (CDCl.sub.3) 6.52 (t,
J=3 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.50 (t, J=8 Hz, 1H) 7.62 (t, J=8 hz, 1H), 7.81 (m, 2H), 8.12 (d, J=8 Hz, 1H).


N-Benzo[1,3]dioxol-5-ylmethyl-N-benzyl-2-pyrazol-1-yl-benzamide, Compound 179 1.1 equiv of carbonyl diimidazole is added to a solution of benzoic acid 178 (200 mg) in tetrahydrofuran (5 mL); the reaction is stirred at room temperaturte for 3 h.
After this time N-piperonyl-N-benzylamine (0.25 g) is added in one portion.  After 30 min, the reaction is filtered, diluted with ether and washed with water.  The organic layer is dried (Na.sub.2 SO.sub.4) and purified over column chromatography to
provide the desired product (390 mg).  The proton NMR displays a typically doubled pattern.  .sup.1 H (CDCl.sub.3) 3.83 and 4.32 (two doublets, J=16 Hz, 1H), 3.91 (two doublets, J=8 Hz, 1H), 4.18 two doublets (J=6 Hz, 1H), 5.0 and 5.1 (two doublets, J=14
Hz, 1H), 5.93 and 5.98 (s and doublet, J=2 Hz, 2H, OCH.sub.2 O), 6.35-6.40 (m, 2H), 6.51 (d, J=4 Hz, 0.5H), 6.4 (m, 1.5H), 7.0-7.88 m, 15H).  LC-MS 412.3.  ##STR249##


Example 11


Preparation of N-Benzoyl-N-(4-methoxybenzyl)-N-(1-propyl-2methyleno-7-azabenzimidazole


2Aminopropyl-3-nitropyridine ##STR250##


2-chloro-3-nitroaminopyridine (180) (5.5 g, 35 mmol) is dissolved in 150 mL acetonitrile at room temperature.  Propylamine (21 g, 350 mmol) is added dropwise and the reaction mixture is stirred for 5 hours at room temperature.  The solvent and
excess propylamine are removed in vacuo.  The residue is dissolved in 150 mL ethyl acetate and washed once with 100 mL saturated NaHCO.sub.3 solution and once with 100 mL brine.  The organic layer is dried over MgSO.sub.4, filtered, and the solvent
removed in vacuo to afford 6.3 g of 2-aminopropyl-3-nitropyridine (181).


2-Aminopropyl-3-aminopyridine.  ##STR251##


2-aminopropyl-3-nitropyridine (171)(6.3 g, 35 mmol) is dissolved in 100 mL 1/1 ethyl acetate/ethanol in a Parr shaker bottle.  Nitrogen is bubbled through the solution for 2 minutes followed by the addition of 10% Pd/C (500 mg).  The suspension
is hydrogenated on a Parr apparatus under 40 psi of H.sub.2 until hydrogen uptake ceased.  The suspension is filtered through Celite and the solvent evaporated in vacuo to afford 5.3 g of the 2-aminopropyl-3-aminopyridine (182).


1-Propyl-2-chloromethyl-7-azabenzimidazole ##STR252##


2-aminopropyl-3-aminopyridine (172) (5.3 g, 35 mmol) is dissolved in 100 mL CHCl.sub.3 at room temperature.  Ethylchloromethylimidate hydrochloride (14 g, 89 mmol) is added followed by K.sub.2 CO.sub.3 (25 g, 180 mmol).  The suspension was
stirred vigorously at room temperature for 3 hours.  The reaction mixture is filtered through Celite and the, solvent removed in vacuo.  The residue is passed through a short plug of silica gel eluting with ethyl acetate to afford 3.7 g of
1-propyl-2-chloromethyl-7-azabenzimidazole (183).


1-Propyl-2-(4-methoxybenzylamino)methyl-7-azabenzimidazole.  ##STR253##


4-Methoxybenzylamine (3.8 g, 27 mmol) is dissolved in 20 mL dry acetonitrile.  1-propyl-2-chloromethyl-7-azabenzimidazole (173)(940 mg, 4.5 mmol) dissolved in 4.5 mL acetonitrile is added dropwise.  The mixture is stirred 10 hours at room
temperature.  The solvent is removed in vacuo and the residue dissolved in 20 mL ethyl acetate.  This solution is washed once with 20 mL 1 N NaOH, once with 20 mL water, once with 20 mL 5% HOAc in water, then once with 5 N NaOH.  The organic phase was
dried over MgSO.sub.4, filtered, then concentrated in vacuo.  The product mixture is purified by flash chromatography eluting with ethyl acetate followed by 95/5/1 ethyl acetate/methanol/triethylamine to afford 850 mg of the
1-propyl-2-(4-methoxybenzylamino)methyl-7-azabenzimidazole (184).


N-Benzoyl-N-(4-methoxybenzyl)-N-(1-propyl-2-methyleno-7-azabenzimidazole ##STR254##


1-propyl-2-(4-methoxybenzylamino)methyl-7-azabenzimidazole (174)(19 mg, 0.06 mmol) is dissolved in 0.6 mL toluene.  Saturated sodium bicarbonate solution in water (0.3 mL) is added followed by benzoyl chloride (11 mg, 0.08 mmol).  The reaction
mixture is stirred at room temperature for 10 hours.  It is then diluted with 5 mL ethyl acetate and transferred to a .  separatory funnel.  The aqueous layer is removed and the organic phase washed once with 1N NaOH, once with 5 mL water, then and once
with mL brine.  The organic phase is dried over MgSO.sub.4, filtered and the solvent removed in vacuo.  The product is purified by preparatory tlc eluting with 1/1 ethyl acetate/hexanes to afford 20 mg of the desired compound (185).  NMR 400 MHz
(CDCl.sub.3) 8.39 ppm (br d, 1H), 8.15 ppm (br d, 1H), 7.52 ppm (m, 1.5H), 7.40 ppm (s, 1.5H), 7.22 (m, 1H), 7.18 ppm (br d, 1H), 6.83 ppm, (d, J=4 Hz, 2H), 4.93 ppm (br s, 2H), 4.71 ppm (br s, 1H), 4.39 ppm (br s, 1H), 3.79 ppm (s, 3H), 1.89 ppm (br m,
2H), 0.98 pp, (br t, 3H).


Example 12


Assay for C5a Receptor Mediated Chemotaxis


This assay is a standard assay of C5a receptor mediated chemotaxis.


Human promonocytic U937 cells or purified human or non-human neutrophilis are treated with dibutyryl cAMP for 48 hours prior to performing the assay.  Human neutrophils or those from another mammalian species are used directly after isolation. 
The cells are pelleted and resuspended in culture media containing 0.1% fetal bovine serum (FBS) and 10 ug/ml calcein AM (a fluorescent dye).  This suspension is then incubated at 37.degree.  C. for 30 minutes such that the cells take up the fluorescent
dye.  The suspension is then centrifuged briefly to pellet the cells, which are then resuspended in culture media containing 0.1% FBS at a concentration of approximately 3.times.10.sup.6 cells/mL.  Aliquots of this cell suspension are transferred to
clean test tubes, which contain vehicle (1% DMSO) or varying concentrations of a compound of interest, and incubated at room temperature for at least 30 minutes.  The chemotaxis assay is performed in ChemoTx.TM.  101-8, 96 well plates (Neuro Probe, Inc. 
Gaitherburg, Md.).  The bottom wells of the plate are filled with medium containing 0-10 nM of C5a, preferably derived from the same species of mammal as are the neutrophils or other cells (e.g., human C5a for the human U937 cells).  The top wells of the
plate are filled with cell suspensions (compound or vehicle-treated).  The plate is then placed in a tissue culture incubator for 60 minutes.  The top surface of the plate is washed with PBS to remove excess cell suspension.  The number of cells that
have migrated into the bottom well is then determined using a fluorescence reader.  Chemotaxis index (the ratio of migrated cells to total number of cells loaded) is then calculated for each compound concentration to determine an IC.sub.50 value.


As a control to ensure that cells retain chemotactic ability in the presence of the compound of interest, the bottom wells of the plate may be filled with varying concentrations chemo-attractants that do not mediate chemotaxis via the C5a
receptor, e.g. zymosan-activated serum (ZAS), N-formylmethionyl-leucyl-phenylalanine (FMLP) or leukotriene B4 (LTB4), rather than C5a, under which conditions the compounds of the invention preferably do not inhibit chemotaxis.


Preferred compounds of the invention exhibit IC.sub.50 values of less than 1 .mu.M in the above assay for C5a mediated chemotaxis.


Example 13


Determination of Dopamine D.sub.4 Receptor Binding Activity


The following assay is a standard assay for determining the binding affinity of compounds to dopamine D.sub.4 receptors.


Pellets of Chinese hamster ovary (CHO) cells containing recombinantly expressing primate dopamine D4 receptors are used for the assays.  The dopamine D.sub.4 receptor expression vector may be the pCD-PS vector described by Van Tol et al. (Nature
(1991) 358: 149-152).  The sample is homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer containing 120 mM NaCl, 5 mM MgCl.sub.2 and 1 mM EDTA at 4.degree.  C. and pH 7.4.  The sample is then centrifuged at 30,000.times.g and resuspended and
rehomogenized.  The sample is then centrifuged as described and the final tissue sample is frozen until use.  The tissue is resuspended 1:20 (wt/vol) in 0.05 M Tris HCl buffer containing 120 mM NaCl.


Incubations for dopaminergic binding are carried out at 25.degree.  C. and contain 0.4 ml of tissue sample, 0.1 nM .sup.3 H-YM 09151-2 (Nemonapride, cis-5-Chloro-2-methoxy-4-(methylamino)-N-(2-methyl-2-(phenylmethyl)-3-pyrr olidinyl)benzamide)
and the compound of interest in a total incubation of 1.0 ml.  Nonspecific binding is defined as that binding found in the presence of 1 uM spiperone; without further additions, nonspecific binding is less than 20% of total binding.


Example 14


Preparation of Radiolabeled Probe Compounds of the Invention


The compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope.  The radioisotope is preferably selected from of at least one of carbon
(preferably .sup.14 C), hydrogen (preferably .sup.3 H), sulfur (preferably .sup.35 S), or iodine (preferably .sup.125 I).  Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled
probe compounds.  Such suppliers include Amersham Corporation, Arlington Heights, Ill.; Cambridge Isotope Laboratories, Inc.  Andover, Mass.; SRI International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento, Calif.; ChemSyn Laboratories,
Lexena, Kans.; American Radiolabeled Chemicals, Inc., St.  Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.  Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid,
acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas.  Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph
using the compound of the invention as substrate.  In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.


Example 15


Baculoviral Preparations (For C5a Expression)


The human C5a (hC5a) receptor baculoviral expression vector was co-transfected along with BACULOGOLD DNA (BD, PharMingen, San Diego, Calif.) into S.function.9 cells.  The S.function.9 cell culture supernatant was harvested three days
post-transfection.  The recombinant virus-containing supernatant was serially diluted in Hink's TNM-FH insect medium (JRH Biosciences, Kansas City) supplemented Grace's salts and with 4.1 mM L-Gln, 3.3 g/L LAH, 3.3 g/L ultrafiltered yeastolate and 10%
heat-inactivated fetal bovine serum (hereinafter "insect medium") and plaque assayed for recombinant plaques.  After four days, recombinant plaques were selected and harvested into 1 ml of insect medium for amplification.  Each 1 ml volume of recombinant
baculovirus (at passage 0) was used to infect a separate T25 flask containing 2.times.10.sup.6 S.function.9 cells in 5 mls of insect medium.  After five days of incubation at 27.degree.  C., supernatant medium was harvested from each of the T25
infections for use as passage 1 inoculum.  Two of seven recombinant baculoviral clones were then chosen for a second round of amplification, using 1 ml of passage 1 stock to infect 1.times.10.sup.8 cells in 100 ml of insect medium divided into 2 T175
flasks.  Forty-eight hours post infection, passage 2 medium from each 100 ml prep was harvested and plaque assayed for titer.  The cell pellets from the second round of amplification were assayed by affinity binding as described below to verify
recombinant receptor expression.  A third round of amplification was then initiated using a multiplicity of infection of 0.1 to infect a liter of S.function.9 cells.  Forty hours post-infection the supernatant medium was harvested to yield passage 3
baculoviral stock.


The remaining cell pellet is assayed for affinity binding using the "Binding Assays" described by DeMartino et al., 1994, J. Biol.  Chem. 269#20, pp.14446-14450 at page 14447, adapted as follows.  Radioligand is 0.005-0.500 nM [.sup.125 I]C5a
(human recombinant), New England Nuclear Corp., Boston, Mass.; the hC5a receptor-expressing baculoviral cells are used instead of 293 cells; the assay buffer contains 50 mM Hepes pH.  7.6, 1 mM CaCl.sub.2, 5 mM MgCl.sub.2, 0.1% BSA, pH 7.4, 0.1 mM
bacitracin, and 100 KIU/ml aprotinin; filtration is carried out using GF/C WHATMAN filters (presoaked in 1.0% polyethyeneimine for 2 hours prior to use); and the filters are washed twice with 5 mLs cold binding buffer without BSA, bacitracin, or
aprotinin.  Titer of the passage 3 baculoviral stock is determined by plaque assay and a multiplicity of infection, incubation time course, binding assay experiment is carried out to determine conditions for optimal receptor expression.


A multiplicity of infection of 0.1 and a 72-hour incubation were the best infection parameters found for hC5a receptor expression -in up to 1-liter S.function.9 cell infection cultures.


Example 16


Baculoviral Infections


Log-phase S.function.9 cells (INVITROGEN Corp., Carlsbad Calif.), are infected with one or more stocks of recombinant baculovirus followed by culturing in insect medium at 27.degree.  C. Infections are carried out either only with virus directing
the expression of the hC5a receptor or with this virus in combination with three G-protein subunit-expression virus stocks: 1) rat Ga.sub.i2 G-protein-encoding virus stock (BIOSIGNAL #V5J008), 2) bovine b1 G-protein-encoding virus stock (BIOSIGNAL
#V5H012), and 3) human g2 G-protein-encoding virus stock (BIOSIGNAL #V6B003), which may be obtained from BIOSIGNAL Inc., Montreal.


The infections are conveniently carried out at a multiplicity of infection of 0.1:1.0:0.5:0.5.  At 72 hours post-infection, a sample of cell suspension is analyzed for viability by trypan blue dye exclusion, and the remaining S.function.9 cells
are harvested via centrifugation (3000 rpm/ 10 minutes/ 4.degree.  C.).


Example 17


Purified Recombinant Insect Cell Membranes


S.function.9 cell pellets are resuspended in homogenization buffer (10 mM HEPES, 250 mM sucrose, 0.5 yg/ml leupeptin, 2 yg/ml Aprotinin, 200 yM PMSF, and 2.5 mM EDTA, pH 7.4) and homogenized using a POLYTRON homogenizer (setting 5 for 30
seconds).  The homogenate is centrifuged (536.times.g/10 minutes/4.degree.  C.) to pellet the nuclei.  The supernatant containing isolated membranes is decanted to a clean centrifuge tube, centrifuged (48,000.times.g/30 minutes, 4.degree.  C.) and the
resulting pellet resuspended in 30 ml homogenization buffer.  This centrifugation and resuspension step is repeated twice.  The final pellet is resuspended in ice cold Dulbecco's PBS containing 5 mM EDTA and stored in frozen aliquots at -80.degree.  C.
until needed.  The protein concentration of the resulting membrane preparation (hereinafter "P2 membranes") is conveniently measured using a Bradford protein assay (Bio-Rad Laboratories, Hercules, Calif.).  By this measure, a 1-liter culture of cells
typically yields 100-150 mg of total membrane protein.


Example 18


Agonist-Induced GTP Binding


Agonist-stimulated GTP-gamma.sup.35 S binding ("GTP binding") activity-can be used to identify agonist and antagonist compounds and to differentiate neutral antagonist compounds from those that possess inverse agonist activity.  This activity can
also be used to detect partial agonism mediated by antagonist compounds.  A compound being analyzed in this assay is referred to herein as a "test compound." Agonist-stimulated GTP binding activity is measured as follows: Four independent baculoviral
stocks (one directing the expression of the hC5a receptor and three directing the expression of each of the three subunits of a heterotrimeric G-protein) are used to infect a culture of S.function.9 cells as described in Example 16.


Agonist-stimulated GTP binding on purified membranes (prepared as described in Example 17) is assessed using hC5a (Sigma Chemical Co., St.  Louis, Mo., USA) as agonist in order to ascertain that the receptor/G-protein-alpha-beta-gamma
combination(s) yield a functional response as measured by GTP binding.


P2 membranes are resuspended by Dounce homogenization (tight pestle) in GTP binding assay buffer (50 mM Tris pH 7.0, 120 mM NaCl, 2 mM MgC12, 2 mM EGTA, 0.1% BSA, 0.1 mM bacitracin, 100KIU/mL aprotinin, 5 .mu.M GDP) and added to reaction tubes at
a concentration of 30 ug protein/reaction tube.  After adding increasing doses of the agonist hC5a at concentrations ranging from 10.sup.-12 M to 10.sup.-6 M, reactions are initiated by the addition of 100 pM GTP gamma.sup.35 S. In competition
experiments, non-radiolabeled test compounds (e.g., compounds of the invention) are added to separate assays at concentrations ranging from 10.sup.-10 M to 10.sup.-5 M along with 10 nM hC5a to yield a final volume of 0.25 mL.


Neutral antagonists are those test compounds that reduce the C5a-stimulated GTP binding activity towards, but not below, baseline (the level of GTP bound by membranes in this assay in the absence of added C5a or other agonist and in the further
absence of any test compound).


In contrast, in the absence of added C5a certain preferred compounds of the invention will reduce the GTP binding activity of the receptor-containing membranes below baseline, and are thus characterized as inverse agonists.  If a test compound
that displays antagonist activity does not reduce the GTP binding activity below baseline in the absence of the C5a agonist, it is characterized as a neutral antagonist.


An antagonist test compound elevates GTP binding activity above baseline in the absence of added hC5a in this GTP binding assay is characterized as having partial agonist activity.  Preferred antagonist compounds of the invention do not elevate
GTP binding activity under such.conditions more than 10% above baseline, preferably not more than 5% above baseline, and most preferably not more than 2% above baseline.


Following a 60-minute incubation at room temperature, the reactions are terminated by vacuum filtration over GF/C filters (pre-soaked in wash buffer, 0.1% BSA) followed by washing with ice-cold wash buffer (50 mM Tris pH 7.0, 120 mM NaCl).  The
amount of receptor-bound (and thereby membrane-bound) GTP gamma.sup.35 s is determined by measuring the bound radioactivity, preferably by liquid scintillation spectrometry of the washed filters.  Non-specific binding is determined using 10 mM GTP
gamma.sup.35 S and typically represents less than 5 percent of total binding.  Data is expressed as percent above basal (baseline).  The results of these GTP binding experiments may be conveniently analyzed using SIGMAPLOT software (SPSS Inc., Chicago,
Ill., USA).


Example 19


Calcium Mobilization Assays


A. Response to C5a


U937 cells are grown in differentiation media (1 mM dibutyrl cAMP in RPMI 1640 medium containing 10% fetal bovine serum) for 48 hrs at 37.degree.  C. then reseeded onto 96-well plates suitable for use in a FLIPR.TM.  Plate Reader (Molecular
Devices Corp., Sunnyvale Calif.).  Cells are grown an additional 24 hours (to 70-90% confluence) before the assay.  The cells are then washed once with Krebs Ringer solution.  Fluo-3 calcium sensitive dye (Molecular Probes, Inc.  Eugene, Oreg.) is added
to 10 ug/mL and incubated with the cells at room temperature for 1 to 2 hours.  The 96 well plates are then washed to remove excess dye.  Fluorescence responses, measured by excitation at 480 nM and emission at 530 nM, are monitored upon the addition of
human C5a to the cells to a final concentration of 0.01-30.0 nM, using the FLIPR.TM.  device (Molecular Devices).  Differentiated U937 cells typically exhibit signals of 5,000-50,000 Arbitrary Fluorescent Light Units in response to agonist stimulation.


B. Assays for Determination of ATP Responses


Differentiated U937 cells (prepared and tested as described above under "A. Response to C5a") are stimulated by the addition of ATP (rather than C5a) to a final concentration of 0.01 to 30 uM.  This stimulation typically triggers a signal of
1,000 to 12,000 arbitrary fluorescence light units.  Certain preferred compounds of the invention produce less than a 10%, preferably less than a 5%, and most preferably less than a 2% alteration of this calcium mobilization signal when this control
assay is carried out in the presence or absence of the compounds.


C. Assays for the Identification of Receptor Modulatory Agents: Antagonists and Agonists


Those of skill in the art will recognize that the calcium mobilization assay described above may be readily adapted for identifying test compounds as having agonist or antagonist activity, at the human C5a receptor.


For example, in order to identify antagonist compounds, differentiated U937 cells are washed and incubated with Fluo-3 dye as described above.  One hour prior to measuring the fluorescence signal, a subset of the cells is incubated with a 1 M
concentration of at least one compound to be tested.  The fluorescence response upon the subsequent addition of 0.3 nM (final concentration) human recombinant C5a is monitored using the FLIPR.TM.  plate reader.  Antagonist compounds elicit at least a
2-fold decrease in the fluorescence response relative to that measured in the presence of human C5a alone.  Preferred antagonist compounds elicit at least a 5-fold, preferably at least a 10-fold, and more preferably at least a 20-fold decrease in the
fluorescence response relative to that measured in the presence of human C5a alone.  Agonist compounds elicit an increase in fluorescence without the addition of C5a, which increase will be at least partially blocked by a known C5a receptor antagonist.


Example 20


Assays to Evaluate Agonist Activity of Small Molecule C5a Receptor Antagonists


Preferred compounds of the invention are C5a receptor antagonists that do not possess significant (e.g., greater than 5%) agonist activity in any of the C5a mediated functional assays discussed herein.  Specifically, this undesired agonist
activity can be evaluated, for example, in the GTP binding assay of Example 18, by measuring small molecule mediated GTP binding in the absence of the natural agonist, C5a.  Similarly, in a calcium mobilization assay e.g., that of Example 19, a small
molecule compound can be directly assayed for the ability of the compound to stimulate calcium levels in the absence of the natural agonist, C5a.  The preferred extent of C5a agonist activity exhibited by compounds of the invention is less than 10%, more
preferably less than 5% and most preferably less than 2% of the response elicited by the natural agonist, C5a.


Example 21


Expression of a C5a Receptor


A human C5a receptor cDNA was obtained by PCR using 1) a forward primer adding a Kozak ribosome binding site and 2) a reverse primer that added no additional sequence, and 3) an aliquot of a Stratagene Human Fetal Brain cDNA library as template. 
The sequence of the resulting PCR product is set forth as SEQ ID NO:1.  The PCR product was subcloned into the cloning vector pCR-Script AMP (STRATAGENE, La Jolla, Calif.) at the Srf I site.  It was then excised using the restriction enzymes EcoRI and
NotI and subcloned in the appropriate orientation for expression into the baculoviral expression vector pBacPAK 9 (CLONTECH, Palo Alto, Calif.) that had been digested with EcoRI and NotI.


Example 22


Radioligand Binding Assays


Purified P2 membranes, prepared by the method given above, are resuspended by Dounce homogenization (tight pestle) in binding buffer (50 mM Hepes pH.  7.6, 120 mM NaCl, 1 mM CaCl.sub.2, 5 mM MgCl.sub.2, 0.1% BSA, pH 7.4, 0.1 mM bacitracin, 100
KIU/ml aprotinin).


For saturation binding analysis, membranes (5-50 .mu.g) are added to polypropylene tubes containing 0.005-0.500 nM [.sup.125 I]C5a (human (recombinant), New England Nuclear Corp., Boston, Mass.).  Nonspecific binding is determined in the presence
of 300 nM hC5a (Sigma Chemical Co., St.  Louis, Mo.) and accounted for less than 10% of total binding.  For evaluation of guanine nucleotide effects on receptor affinity, GTP.gamma.S is added to duplicate tubes at the final concentration of 50 .mu.M.


For competition analysis, membranes (5-50 .mu.g) are added to polypropylene tubes containing 0.030 nM [.sup.125 I]C5a (human).  Non-radiolabeled displacers are added to separate assays at concentrations ranging from 10.sup.-10 M to 10.sup.-5 M to
yield a final volume of 0.250 mL.  Nonspecific binding is determined in the presence of 300 nM hC5a (Sigma Chemical Co., St.  Louis, Mo.) and accounted for less than 10% of total binding.  Following a 2-hour incubation at room temperature, the reaction
is terminated by rapid vacuum filtration.  Samples are filtered over presoaked (in 1.0% polyethyleneimine for 2 hours prior to use) GF/C WHATMAN filters and rinsed 2 times with 5 mLs cold binding buffer without BSA, bacitracin, or aprotinin.  Remaining
bound radioactivity is quantified by gamma counting.  K.sub.I and Hill coefficient ("nH") are determined by fitting the Hill equation to the measured values with the aid of SIGMAPLOT software.


As set forth in the tables appended hereto, R groups do not necessarily correlate with those R groups shown in the text of the specification or in the claims.


The following table 1 (214-323) is a list of preferred 1,2,5 substituted imidazoles of the present invention;


The following table 2 (324-429) is a list of preferred 1,2,4,5 substituted imidazoles of the present invention;


The following table 3 (430-431) is a list of preferred pyrazoles of the present invention;


The following table 4 (432-433) is another list of preferred 1,2,4,5 substituted imidazoles of the present invention;


The following table 5 (434-464) is a list of preferred amides of the present invention; and


The following table 6 (456-468) is a list of preferred amides of the present invention.


Additional Aspects of Preferred Compounds of the Invention


The most preferred compounds of the invention are suitable for pharmaceutical use in treating human patients.  Accordingly, such preferred compounds do not exhibit single or multiple dose acute or long-term toxicity, mutagenicity (e.g., as
determined in a bacterial reverse mutation assay such as an Ames test), teratogenicity, tumorogenicity, or the like, and rarely trigger adverse effects (side effects) when administered at therapeutically effective dosages.  For example, preferred
compounds of the invention will not prolong heart QT intervals (e.g., as determined by electrocardiography, e.g., in guinea pigs, minipigs or dogs).  Therapeutically effective doses or concentrations of such compounds do not cause liver enlargement when
fed to or injected into laboratory animals (e.g., mice or rats) and do not promote the release of liver enzymes (e.g., ALT, LDH, or AST) from hepatocytes in vitro or in vivo.


Because side effects are often due to undesirable receptor activation or antagonism, preferred compounds of the invention exert their receptor-modulatory effects with high specificity.  This means that they only bind to, activate, or inhibit the
activity of certain receptors other than C5a receptors with affinity constants of greater than 100 nanomolar, preferably greater than 1 micromolar, more preferably greater than 10 micromolar and most preferably greater than 100 micromolar.  Such
receptors preferably are selected from neurotransmitter receptors such as alpha- or beta-adrenergic receptors, muscarinic receptors (particularly m1, m2, or m3 receptors), dopamine receptors, and metabotropic glutamate receptors; and also include
histamine receptors and cytokine receptors; e.g., interleukin receptors, particularly IL-8 receptors.  Such receptors may also include GABAA receptors, bioactive peptide receptors (other than C5a receptors, including NPY or VIP receptors), neurokinin
receptors, bradykinin receptors, hormone receptors (e.g., CRF receptors, thyrotropin releasing hormone receptors, or melanocyte-concentrating hormone receptors).


Additionally, preferred compounds of the invention do not inhibit or induce microsomal cytochrome P450 enzyme activities, such as CYP1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity, or CYP3A4
activity.  Preferred compounds of the invention also do not exhibit cytotoxicity in vitro or in vivo, are not clastogenic, e.g., as determined using a mouse erythrocyte precursor cell micronucleus assay, an Ames micronucleus assay, a spiral micronucleus
assay, or the like and do not induce sister chromatid exchange, e.g., in Chinese hamster ovary cells.


Highly preferred C5a receptor antagonist compounds of the invention also inhibit the occurrence of C5a-induced oxidative burst (OB) in inflammatory cells, e.g., neutrophil, as can be conveniently determined using an in vitro neutrophil OB assay.


Initial characterization of preferred compounds of the invention can be conveniently carried out using a C5a receptor binding assay or functional assay, such as set forth in the Examples, and may be expedited by applying such assays in a high
throughput screening setting.


The foregoing description is illustrative thereof, and it understood that variations and modifcation can be effected without departing from the scope or spirit of the inveniton as set forth in the following claims.


 TABLE 1  ##STR255##  CMP # R1 R2 R3  R4 R5  Rtn Time Cmd Mass H+ Ion Obs  200 ##STR256## ##STR257##  ##STR258## ##STR259##  1.95 448.2627 449.3036  201 ##STR260## ##STR261##  ##STR262## ##STR263##  1.96 462.2784 463.3201  202 ##STR264##
##STR265##  ##STR266## ##STR267##  1.91 462.2784 463.3241  203 ##STR268## ##STR269##  ##STR270## ##STR271##  2.09 459.2675 460.3053  204 ##STR272## ##STR273##  ##STR274## ##STR275##  2.1 459.2675 460.2983  205 ##STR276## ##STR277##  ##STR278## ##STR279## 2.04 467.2573 468.2888  206 ##STR280## ##STR281##  ##STR282## ##STR283##  2.05 481.2729 482.3052  207 ##STR284## ##STR285##  ##STR286## ##STR287##  2 467.2573 468.2885  208 ##STR288## ##STR289##  ##STR290## ##STR291##  1.96 453.2416 454.2695  209
##STR292## ##STR293##  ##STR294## ##STR295##  1.9 375.2675 376.2897  210 ##STR296## ##STR297##  ##STR298## ##STR299##  2 453.2416 454.2688  211 ##STR300## ##STR301##  ##STR302## ##STR303##  1.9 434.247 435.2789  212 ##STR304## ##STR305##  ##STR306##
##STR307##  1.92 492.2525 493.2912  213 ##STR308## ##STR309##  ##STR310## ##STR311##  1.94 469.2729 470.2986  214 ##STR312## ##STR313##  ##STR314## ##STR315##  1.97 497.2314 498.2636  215 ##STR316## ##STR317##  ##STR318## ##STR319##  2.06 473.3042
474.3346  216 ##STR320## ##STR321##  ##STR322## ##STR323##  2.03 445.2729 446.302  217 ##STR324## ##STR325##  ##STR326## ##STR327##  2.1 477.258 478.2953  218 ##STR328## ##STR329##  ##STR330## ##STR331##  2.01 485.2479 486.2815  219 ##STR332## ##STR333## ##STR334## ##STR335##  2.01 471.2322 472.266  220 ##STR336## ##STR337##  ##STR338## ##STR339##  1.8 438.2784 439.3118  221 ##STR340## ##STR341##  ##STR342## ##STR343##  1.78 438.2784 439.313  222 ##STR344## ##STR345##  ##STR346## ##STR347##  1.86 452.294
453.3306  223 ##STR348## ##STR349##  ##STR350## ##STR351##  2.08 459.2886 460.3148  224 ##STR352## ##STR353##  ##STR354## ##STR355##  1.99 459.1981 460.226  225 ##STR356## ##STR357##  ##STR358## ##STR359##  1.86 419.2573 420.2867  226 ##STR360##
##STR361##  ##STR362## ##STR363##  1.79 405.2416 406.2684  227 ##STR364## ##STR365##  ##STR366## ##STR367##  2.08 521.1637 522.2009  228 ##STR368## ##STR369##  ##STR370## ##STR371##  1.91 513.2628 514.2951  229 ##STR372## ##STR373##  ##STR374##
##STR375##  2.02 461.2467 462.2794  230 ##STR376## ##STR377##  ##STR378## ##STR379##  2 461.2467 462.2892  231 ##STR380## ##STR381##  ##STR382## ##STR383##  2.05 465.2239 466.267  232 ##STR384## ##STR385##  ##STR386## ##STR387##  2.1 477.1739 478.2021 
233 ##STR388## ##STR389##  ##STR390## ##STR391##  1.98 462.2784 463.3135  234 ##STR392## ##STR393##  ##STR394## ##STR395##  235 ##STR396## ##STR397##  ##STR398## ##STR399##  2.07 535.1793 536.2415  236 ##STR400## ##STR401##  ##STR402## ##STR403##  2.11
495.2886 496.3355  237 ##STR404## ##STR405##  ##STR406## ##STR407##  238 ##STR408## ##STR409##  ##STR410## ##STR411##  2 483.2522 484.3027  239 ##STR412## ##STR413##  ##STR414## ##STR415##  1.87 482.3046 483.3743  240 ##STR416## ##STR417##  ##STR418##
##STR419##  1.98 527.242 528.2967  241 ##STR420## ##STR421##  ##STR422## ##STR423##  1.85 482.3046 483.3671  242 ##STR424## ##STR425##  ##STR426## ##STR427##  2.01 483.2522 484.3157  243 ##STR428## ##STR429##  ##STR430## ##STR431##  1.87 482.3046
483.3743  244 ##STR432## ##STR433##  ##STR434## ##STR435##  1.98 515.222 516.2815  245 ##STR436## ##STR437##  ##STR438## ##STR439##  2.01 467.2573 468.3038  246 ##STR440## ##STR441##  ##STR442## ##STR443##  2 511.2471 512.3024  247 ##STR444## ##STR445## 
##STR446## ##STR447##  1.99 471.2322 472.2836  248 ##STR448## ##STR449##  ##STR450## ##STR451##  1.98 515.222 516.2795  249 ##STR452## ##STR453##  ##STR454## ##STR455##  2.01 483.2522 484.3008  250 ##STR456## ##STR457##  ##STR458## ##STR459##  2.06
503.2573 504.3187  251 ##STR460## ##STR461##  ##STR462## ##STR463##  2.08 477.258 478.3242  252 ##STR464## ##STR465##  ##STR466## ##STR467##  1.95 496.2838 497.3316  253 ##STR468## ##STR469##  ##STR470## ##STR471##  1.93 496.2838 497.3374  254 ##STR472##
##STR473##  ##STR474## ##STR475##  1.99 439.2624 440.3063  255 ##STR476## ##STR477##  ##STR478## ##STR479##  2.05 487.2027 488.258  256 ##STR480## ##STR481##  ##STR482## ##STR483##  2.1 443.1895 444.2521  257 ##STR484## ##STR485##  ##STR486## ##STR487## 
2 439.2624 440.3058  258 ##STR488## ##STR489##  ##STR490## ##STR491##  1.78 504.2525 505.3246  259 ##STR492## ##STR493##  ##STR494## ##STR495##  1.97 459.2077 460.287  260 ##STR496## ##STR497##  ##STR498## ##STR499##  2.06 477.1739 478.2339  261
##STR500## ##STR501##  ##STR502## ##STR503##  2.06 461.2034 462.2581  262 ##STR504## ##STR505##  ##STR506## ##STR507##  263 ##STR508## ##STR509##  ##STR510## ##STR511##  1.78 480.3253 481.4043  264 ##STR512## ##STR513##  ##STR514## ##STR515##  1.75
410.247 411.2961  265 ##STR516## ##STR517##  ##STR518## ##STR519##  2.01 503.2339 504.2863  266 ##STR520## ##STR521##  ##STR522## ##STR523##  2.07 493.2341 494.2973  267 ##STR524## ##STR525##  ##STR526## ##STR527##  1.88 425.2467 426.2948  268 ##STR528##
##STR529##  ##STR530## ##STR531##  2.05 443.2128 444.2672  269 ##STR532## ##STR533##  ##STR534## ##STR535##  2.04 461.2034 462.255  270 ##STR536## ##STR537##  ##STR538## ##STR539##  2.1 477.1739 478.2429  271 ##STR540## ##STR541##  ##STR542## ##STR543## 
2.06 521.1637 522.2083  272 ##STR544## ##STR545##  ##STR546## ##STR547##  2.02 479.2573 480.2964  273 ##STR548## ##STR549##  ##STR550## ##STR551##  2.03 433.2729 434.3264  274 ##STR552## ##STR553##  ##STR554## ##STR555##  1.9 433.2729 434.3161  275
##STR556## ##STR557##  ##STR558## ##STR559##  1.74 424.2627 425.298  276 ##STR560## ##STR561##  ##STR562## ##STR563##  1.98 454.2369 455.2756  277 ##STR564## ##STR565##  ##STR566## ##STR567##  2.09 495.1644 496.227  278 ##STR568## ##STR569##  ##STR570##
##STR571##  1.86 470.2846 471.3502  279 ##STR572## ##STR573##  ##STR574## ##STR575##  2.07 496.3002 497.375  280 ##STR576## ##STR577##  ##STR578## ##STR579##  2.02 487.2027 488.2712  281 ##STR580## ##STR581##  ##STR582## ##STR583##  2.02 501.2183
502.2874  282 ##STR584## ##STR585## ##STR586##


 ##STR587## ##STR588##  283 ##STR589## ##STR590##  ##STR591## ##STR592##  2.01 459.2886 460.3366  284 ##STR593## ##STR594##  ##STR595## ##STR596##  2 473.3042 474.3561  285 ##STR597## ##STR598##  ##STR599## ##STR600##  2.1 465.3144 466.3706  286
##STR601## ##STR602##  ##STR603## ##STR604##  287 ##STR605## ##STR606##  ##STR607## ##STR608##  1.99 503.2784 504.3394  288 ##STR609## ##STR610##  ##STR611## ##STR612##  289 ##STR613## ##STR614##  ##STR615## ##STR616##  1.99 459.2886 460.3446  290
##STR617## ##STR618##  ##STR619## ##STR620##  2.07 447.2886 448.3387  291 ##STR621## ##STR622##  ##STR623## ##STR624##  2.06 481.2729 482.3294  292 ##STR625## ##STR626##  ##STR627## ##STR628##  2.08 475.3199 476.3839  293 ##STR629## ##STR630## 
##STR631## ##STR632##  2.11 473.3042 474.361  294 ##STR633## ##STR634##  ##STR635## ##STR636##  1.76 417.2416 418.2879  295 ##STR637## ##STR638##  ##STR639## ##STR640##  2.05 423.2675 424.2875  296 ##STR641## ##STR642##  ##STR643## ##STR644##  2.06
467.2573 468.2819  297 ##STR645## ##STR646##  ##STR647##  2.01 413.2831 414.3154  298 ##STR648## ##STR649##  ##STR650## ##STR651##  2.05 467.2573 468.2849  299 ##STR652## ##STR653##  ##STR654## ##STR655##  2.02 451.2624 452.2898  300 ##STR656##
##STR657##  ##STR658## ##STR659##  2.02 477.1983 478.2289  301 ##STR660## ##STR661##  ##STR662## ##STR663##  2.01 477.1983 478.2308  302 ##STR664## ##STR665##  ##STR666## ##STR667##  1.95 495.2522 496.3082  303 ##STR668## ##STR669## ##STR670## 
##STR671## ##STR672##  1.99 529.2377 530.2964  304 ##STR673## ##STR674## ##STR675##  ##STR676## ##STR677##  2.01 485.2479 486.3004  305 ##STR678## ##STR679## ##STR680##  ##STR681## ##STR682##  2.05 477.2791 478.3398  306 ##STR683## ##STR684## ##STR685## 
##STR686## ##STR687##  307 ##STR688## ##STR689## ##STR690##  ##STR691## ##STR692##  1.99 491.214 492.2748  308 ##STR693## ##STR694##  ##STR695## ##STR696##  1.91 425.2234 426.2757  309 ##STR697## ##STR698##  ##STR699## ##STR700##  1.69 425.2579 426.3054 
310 ##STR701## ##STR702##  ##STR703## ##STR704##  1.96 503.1879 504.2485  311 ##STR705## ##STR706##  ##STR707## ##STR708##  1.98 459.1981 460.2525  312 ##STR709## ##STR710##  ##STR711## ##STR712##  1.99 451.2293 452.2899  313 ##STR713## ##STR714## 
##STR715## ##STR716##  1.99 469.2529 470.3111  314 ##STR717## ##STR718## ##STR719##  ##STR720## ##STR721##  2.01 483.2686 484.3253  315 ##STR722## ##STR723## ##STR724##  ##STR725## ##STR726##  1.78 512.3315 513.4124  316 ##STR727## ##STR728##  ##STR729##
##STR730##  1.81 432.3253 433.3902  317 ##STR731## ##STR732##  ##STR733## ##STR734##  1.83 450.3159 451.3883  318 ##STR735## ##STR736##  ##STR737## ##STR738##  1.97 506.2682 507.3284  319 ##STR739## ##STR740##  ##STR741## ##STR742##  1.95 503.1976
504.2582  320 ##STR743## ##STR744## ##STR745##  ##STR746## ##STR747##  1.97 535.2038 536.2633  321 ##STR748## ##STR749##  ##STR750## ##STR751##  1.93 493.2729 494.3287  322 ##STR752## ##STR753##  ##STR754## ##STR755##  2.06 491.214 492.2753  323
##STR756## ##STR757## ##STR758##  ##STR759## ##STR760##  2.02 471.2453 472.317  324 ##STR761## ##STR762##  ##STR763## ##STR764##  1.92 443.214 444.2721  325 ##STR765## ##STR766## ##STR767##  ##STR768## ##STR769##  1.98 457.2296 458.2892  326 ##STR770##
##STR771##  ##STR772## ##STR773##  1.97 457.2296 458.2943  327 ##STR774## ##STR775##  ##STR776## ##STR777##  1.87 449.2842 450.3473  328 ##STR778## ##STR779## ##STR780##  ##STR781## ##STR782##  2.1 475.1957 476.2632  329 ##STR783## ##STR784##  ##STR785##
##STR786##  2.02 423.2675 424.3092  330 ##STR787## ##STR788##  ##STR789## ##STR790##  331 ##STR791## ##STR792## ##STR793##  ##STR794## ##STR795##  1.98 491.214 492.2755  332 ##STR796## ##STR797## ##STR798##  ##STR799## ##STR800##  1.99 491.214 492.2755 
333 ##STR801## ##STR802##  ##STR803## ##STR804##  2.02 547.2635 548.3262  334 ##STR805## ##STR806##  ##STR807## ##STR808##  2.08 577.1729 578.25  335 ##STR809## ##STR810## ##STR811##  ##STR812## ##STR813##  1.96 511.2471 512.298  336 ##STR814##
##STR815## ##STR816##  ##STR817## ##STR818##  1.95 517.2132 518.2731  337 ##STR819## ##STR820## ##STR821##  ##STR822## ##STR823##  2.15 521.3173 522.3696  338 ##STR824## ##STR825## ##STR826##  ##STR827## ##STR828##  2.15 515.3512 516.4249  339 ##STR829##
##STR830## ##STR831##  ##STR832## ##STR833##  1.88 483.2522 484.3056  340 ##STR834## ##STR835## ##STR836##  ##STR837## ##STR838##  2.05 487.3563 488.4303  341 ##STR839## ##STR840## ##STR841##  ##STR842## ##STR843##  2.08 515.3512 516.4047  342 ##STR844##
##STR845## ##STR846##  ##STR847## ##STR848##  2.05 501.3719 502.4088  343 ##STR849## ##STR850##  ##STR851## ##STR852##  1.97 467.2573 468.2854  344 ##STR853## ##STR854##  ##STR855## ##STR856##  1.94 433.2729 434.297  345 ##STR857## ##STR858##  ##STR859##
##STR860##  2.07 473.3042 474.3316  346 ##STR861## ##STR862##  ##STR863## ##STR864##  2.01 459.2886 460.3174  347 ##STR865## ##STR866##  ##STR867## ##STR868##  1.88 439.2624 440.2939  348 ##STR869## ##STR870##  ##STR871## ##STR872##  1.7 405.278 406.3116 349 ##STR873## ##STR874##  ##STR875## ##STR876##  1.96 445.3093 446.3387  350 ##STR877## ##STR878## ##STR879##  ##STR880## ##STR881##  2.07 523.3199 524.3464  351 ##STR882## ##STR883## ##STR884##  ##STR885## ##STR886##  2.04 489.3355 490.3575  352
##STR887## ##STR888## ##STR889##  ##STR890## ##STR891##  2.15 529.3668 530.3951  353 ##STR892## ##STR893## ##STR894##  ##STR895## ##STR896##  2.01 509.3042 510.337  354 ##STR897## ##STR898## ##STR899##  ##STR900## ##STR901##  2.08 515.3512 516.3834  355
##STR902## ##STR903## ##STR904##  ##STR905## ##STR906##  356 ##STR907## ##STR908## ##STR909##  ##STR910## ##STR911##  357 ##STR912## ##STR913## ##STR914##  ##STR915## ##STR916##  2.07 501.3719 502.3938  358 ##STR917## ##STR918## ##STR919##  ##STR920##
##STR921##  2.08 539.3148 540.3187  359 ##STR922## ##STR923## ##STR924##  ##STR925## ##STR926##  2.04 505.3304 506.3531  360 ##STR927## ##STR928## ##STR929##  ##STR930## ##STR931##  2.16 545.3618 546.3911  361 ##STR932## ##STR933##  ##STR934## ##STR935## 2 483.2522 484.2723  362 ##STR936## ##STR937##  ##STR938## ##STR939##  1.93 449.2679 450.2899  363 ##STR940## ##STR941##  ##STR942## ##STR943##  2.08 489.2991 490.3192  364 ##STR944## ##STR945## ##STR946##  ##STR947## ##STR948##  2.06 525.2991 526.36 
365 ##STR949## ##STR950## ##STR951##  ##STR952## ##STR953##  2.12 531.3461 532.3955  366 ##STR954## ##STR955##  ##STR956## ##STR957##  1.95 469.2365 470.2861  367 ##STR958## ##STR959##  ##STR960## ##STR961##  1.8 435.2622 436.2889  368 ##STR962##
##STR963##


 ##STR964## ##STR965##  2.03 475.2835 476.3151  369 ##STR966## ##STR967## ##STR968##  ##STR969## ##STR970##  1.94 511.3199 512.3583  370 ##STR971## ##STR972## ##STR973##  ##STR974## ##STR975##  1.72 477.3355 478.3816  371 ##STR976## ##STR977##
##STR978##  ##STR979## ##STR980##  1.98 517.3668 518.4061  372 ##STR981## ##STR982## ##STR983##  ##STR984## ##STR985##  2.02 553.3304 554.3617  373 ##STR986## ##STR987## ##STR988##  ##STR989## ##STR990##  1.96 519.3461 520.382  374 ##STR991## ##STR992##
##STR993##  ##STR994## ##STR995##  2.09 559.3774 560.4091  375 ##STR996## ##STR997##  ##STR998## ##STR999##  1.92 497.2679 498.3003  376 ##STR1000## ##STR1001##  ##STR1002## ##STR1003##  2 503.3148 504.343  377 ##STR1004## ##STR1005## ##STR1006## 
##STR1007## ##STR1008##  378 ##STR1009## ##STR1010## ##STR1011##  ##STR1012## ##STR1013##  2 525.3355 526.3682  379 ##STR1014## ##STR1015## ##STR1016##  ##STR1017## ##STR1018##  1.81 491.3512 492.3873  380 ##STR1019## ##STR1020## ##STR1021##  ##STR1022##
##STR1023##  2.05 531.3825 532.415  381 ##STR1024## ##STR1025##  ##STR1026## ##STR1027##  382 ##STR1028## ##STR1029##  ##STR1030## ##STR1031##  1.94 475.3199 476.3517  383 ##STR1032## ##STR1033##  ##STR1034## ##STR1035##  1.86 483.2522 484.2405  384
##STR1036## ##STR1037##  ##STR1038## ##STR1039##  1.94 517.2132 518.2035  385 ##STR1040## ##STR1041##  ##STR1042## ##STR1043##  1.97 497.2679 498.2453  386 ##STR1044## ##STR1045##  ##STR1046## ##STR1047##  1.95 511.2471 512.2275  387 ##STR1048##
##STR1049##  ##STR1050## ##STR1051##  2.06 553.2941 554.2728  388 ##STR1052## ##STR1053##  ##STR1054## ##STR1055##  2.05 519.3097 520.2906  389 ##STR1056## ##STR1057##  ##STR1058## ##STR1059##  2.13 559.341 560.3246  390 ##STR1060## ##STR1061## 
##STR1062## ##STR1063##  1.78 469.2365 470.2381  391 ##STR1064## ##STR1065##  ##STR1066## ##STR1067##  1.88 503.1976 504.1985  392 ##STR1068## ##STR1069##  ##STR1070## ##STR1071##  1.89 483.2522 484.2435  393 ##STR1072## ##STR1073##  ##STR1074##
##STR1075##  1.89 497.2314 498.227  394 ##STR1076## ##STR1077##  ##STR1078## ##STR1079##  1.71 455.2573 456.2579  395 ##STR1080## ##STR1081##  ##STR1082## ##STR1083##  1.84 489.2183 490.22  396 ##STR1084## ##STR1085##  ##STR1086## ##STR1087##  1.85
469.2729 470.2647  397 ##STR1088## ##STR1089##  ##STR1090## ##STR1091##  1.85 483.2522 484.24  398 ##STR1092## ##STR1093## ##STR1094##  ##STR1095## ##STR1096##  1.97 531.3825 532.3688  399 ##STR1097## ##STR1098## ##STR1099##  ##STR1100## ##STR1101## 
2.07 509.3042 510.2987  400 ##STR1102## ##STR1103## ##STR1104##  ##STR1105## ##STR1106##  1.99 481.3093 482.3098  401 ##STR1107## ##STR1108## ##STR1109##  ##STR1110## ##STR1111##  2.05 515.2703 516.2676  402 ##STR1112## ##STR1113## ##STR1114## 
##STR1115## ##STR1116##  2.01 481.3093 482.3063  403 ##STR1117## ##STR1118## ##STR1119##  ##STR1120## ##STR1121##  2.03 523.3199 524.3068  404 ##STR1122## ##STR1123## ##STR1124##  ##STR1125## ##STR1126##  2.04 523.3199 524.3074  405 ##STR1127##
##STR1128## ##STR1129##  ##STR1130## ##STR1131##  1.96 475.3199 476.3177  406 ##STR1132## ##STR1133## ##STR1134##  ##STR1135## ##STR1136##  1.79 447.325 448.3324  407 ##STR1137## ##STR1138## ##STR1139##  ##STR1140## ##STR1141##  2.02 481.286 482.2877 
408 ##STR1142## ##STR1143## ##STR1144##  ##STR1145## ##STR1146##  1.88 447.325 448.326  409 ##STR1147## ##STR1148## ##STR1149##  ##STR1150## ##STR1151##  1.97 489.3355 490.3298  410 ##STR1152## ##STR1153## ##STR1154##  ##STR1155## ##STR1156##  2.01
489.3355 490.3296  411 ##STR1157## ##STR1158## ##STR1159##  ##STR1160## ##STR1161##  2.08 495.325 496.3224  412 ##STR1162## ##STR1163## ##STR1164##  ##STR1165## ##STR1166##  1.92 461.3406 462.3352  413 ##STR1167## ##STR1168## ##STR1169##  ##STR1170##
##STR1171##  2.15 501.3719 502.3614  414 ##STR1172## ##STR1173## ##STR1174##  ##STR1175## ##STR1176##  2.1 515.3124 516.3123  415 ##STR1177## ##STR1178## ##STR1179##  ##STR1180## ##STR1181##  2.08 495.325 496.3181  416 ##STR1182## ##STR1183## ##STR1184## ##STR1185## ##STR1186##  2.01 461.3400 462.3389  417 ##STR1187## ##STR1188## ##STR1189##  ##STR1190## ##STR1191##  2.16 501.3719 502.3629  418 ##STR1192## ##STR1193## ##STR1194##  ##STR1195## ##STR1196##  419 ##STR1197## ##STR1198## ##STR1199## 
##STR1200## ##STR1201##  420 ##STR1202## ##STR1203## ##STR1204##  ##STR1205## ##STR1206##  2.08 514.4036 515.423  421 ##STR1207## ##STR1208## ##STR1209##  ##STR1210## ##STR1211##  2.14 515.3512 516.3379  422 ##STR1212## ##STR1213## ##STR1214## 
##STR1215## ##STR1216##  2.14 521.3173 522.3266  423 ##STR1217## ##STR1218## ##STR1219##  ##STR1220## ##STR1221##


 TABLE 1A  ##STR1222##  R3 is H unless otherwise specified  CMP # R1 R2 R3  R4 R5  Rtn Time Cmd Mass H+ Ion Obs  424 ##STR1223## ##STR1224##  ##STR1225## ##STR1226##  2.02 427.2424 428.2541  425 ##STR1227## ##STR1228##  ##STR1229## ##STR1230## 
2.06 441.258 442.2744  426 ##STR1231## ##STR1232##  ##STR1233## ##STR1234##  2.1 455.2737 456.2899  427 ##STR1235## ##STR1236##  ##STR1237## ##STR1238##  2.08 455.2737 456.2953  428 ##STR1239## ##STR1240##  ##STR1241## ##STR1242##  2.13 469.2893 470.3137 429 ##STR1243## ##STR1244##  ##STR1245## ##STR1246##  2.02 485.2479 486.2833  430 ##STR1247## ##STR1248##  ##STR1249## ##STR1250##  2.15 481.3093 482.332  431 ##STR1251## ##STR1252##  ##STR1253## ##STR1254##  432 ##STR1255## ##STR1256##  ##STR1257##
##STR1258##  1.98 419.2573 420.2856  433 ##STR1259## ##STR1260##  ##STR1261## ##STR1262##  1.91 431.2573 432.2898  434 ##STR1263## ##STR1264##  ##STR1265## ##STR1266##  1.92 433.2729 434.3079  435 ##STR1267## ##STR1268##  ##STR1269## ##STR1270##  1.91
433.2729 434.3078  436 ##STR1271## ##STR1272##  ##STR1273## ##STR1274##  2.04 433.2729 434.3079  437 ##STR1275## ##STR1276##  ##STR1277## ##STR1278##  2.04 401.2831 402.3126  438 ##STR1279## ##STR1280##  ##STR1281## ##STR1282##  2.01 445.2729 446.3118 
439 ##STR1283## ##STR1284##  ##STR1285## ##STR1286##  1.99 447.2886 448.329  440 ##STR1287## ##STR1288##  ##STR1289## ##STR1290##  1.98 447.2886 448.3293  441 ##STR1291## ##STR1292##  ##STR1293## ##STR1294##  1.95 447.2886 448.3331  442 ##STR1295##
##STR1296##  ##STR1297## ##STR1298##  2.06 447.2886 448.3315  443 ##STR1299## ##STR1300##  ##STR1301## ##STR1302##  2.09 403.2987 404.3406  444 ##STR1303## ##STR1304##  ##STR1305## ##STR1306##  2.07 447.2886 448.3385  445 ##STR1307## ##STR1308## 
##STR1309## ##STR1310##  1.99 459.2886 460.3416  446 ##STR1311## ##STR1312##  ##STR1313## ##STR1314##  2.07 459.2886 460.3427  447 ##STR1315## ##STR1316##  ##STR1317## ##STR1318##  2.04 461.3042 462.362  448 ##STR1319## ##STR1320##  ##STR1321##
##STR1322##  2.04 473.3042 474.3634  449 ##STR1323## ##STR1324##  ##STR1325## ##STR1326##  2.12 473.3042 474.3605  450 ##STR1327## ##STR1328##  ##STR1329## ##STR1330##  2.05 473.3042 474.3627  451 ##STR1331## ##STR1332##  ##STR1333## ##STR1334##  2.09
475.3199 476.3831  452 ##STR1335## ##STR1336##  ##STR1337## ##STR1338##  2.09 529.2729 530.334  453 ##STR1339## ##STR1340##  ##STR1341## ##STR1342##  2.09 545.2678 546.3349  454 ##STR1343## ##STR1344##  ##STR1345## ##STR1346##  2.02 423.2675 424.3183 
455 ##STR1347## ##STR1348##  ##STR1349## ##STR1350##  2.01 409.2518 410.3021  456 ##STR1351## ##STR1352##  ##STR1353## ##STR1354##  2.07 459.2675 460.326  457 ##STR1355## ##STR1356##  ##STR1357## ##STR1358##  2 453.2416 454.3023  458 ##STR1359##
##STR1360##  ##STR1361## ##STR1362##  2.06 437.2831 438.3368  459 ##STR1363## ##STR1364##  ##STR1365## ##STR1366##  2.05 423.2675 424.318  460 ##STR1367## ##STR1368##  ##STR1369## ##STR1370##  2.11 473.2831 474.3436  461 ##STR1371## ##STR1372## 
##STR1373## ##STR1374##  2.04 467.2573 468.3188  462 ##STR1375## ##STR1376##  ##STR1377## ##STR1378##  2.06 437.2831 438.3386  463 ##STR1379## ##STR1380##  ##STR1381## ##STR1382##  464 ##STR1383## ##STR1384##  ##STR1385## ##STR1386##  2.11 473.2831
474.3485  465 ##STR1387## ##STR1388##  ##STR1389## ##STR1390##  2.03 467.2573 468.3192  466 ##STR1391## ##STR1392##  ##STR1393## ##STR1394##  2.04 423.2675 424.3211  467 ##STR1395## ##STR1396##  ##STR1397## ##STR1398##  2.1 473.2831 474.3467  468
##STR1399## ##STR1400##  ##STR1401## ##STR1402##  2.02 467.2573 468.3227  469 ##STR1403## ##STR1404##  ##STR1405## ##STR1406##  1.99 471.2322 472.3021  470 ##STR1407## ##STR1408##  ##STR1409## ##STR1410##  2.02 441.258 442.3175  471 ##STR1411##
##STR1412##  ##STR1413## ##STR1414##  1.98 471.2322 472.3026  472 ##STR1415## ##STR1416##  ##STR1417## ##STR1418##  2.03 441.258 442.3185  473 ##STR1419## ##STR1420##  ##STR1421## ##STR1422##  2.01 427.2424 428.3031  474 ##STR1423## ##STR1424## 
##STR1425## ##STR1426##  2.07 477.258 478.3228  475 ##STR1427## ##STR1428##  ##STR1429## ##STR1430##  1.99 471.2322 472.3008  476 ##STR1431## ##STR1432##  ##STR1433## ##STR1434##  2.1 451.2987 452.3606  477 ##STR1435## ##STR1436##  ##STR1437##
##STR1438##  2.08 437.2831 438.351  478 ##STR1439## ##STR1440##  ##STR1441## ##STR1442##  2.14 487.2987 488.3652  479 ##STR1443## ##STR1444##  ##STR1445## ##STR1446##  2.07 481.2729 482.3446  480 ##STR1447## ##STR1448##  ##STR1449## ##STR1450##  2.08
451.2987 452.3621  481 ##STR1451## ##STR1452##  ##STR1453## ##STR1454##  2.08 437.2831 438.346  482 ##STR1455## ##STR1456##  ##STR1457## ##STR1458##  2.14 487.2987 488.3646  483 ##STR1459## ##STR1460##  ##STR1461## ##STR1462##  2.06 481.2729 482.3413 
484 ##STR1463## ##STR1464##  ##STR1465## ##STR1466##  2.09 437.2831 438.3447  485 ##STR1467## ##STR1468##  ##STR1469## ##STR1470##  2.07 481.2729 482.3401  486 ##STR1471## ##STR1472##  ##STR1473## ##STR1474##  2.09 451.2987 452.3614  487 ##STR1475##
##STR1476##  ##STR1477## ##STR1478##  2.08 437.2831 438.3399  488 ##STR1479## ##STR1480##  ##STR1481## ##STR1482##  2.06 481.2729 482.3407  489 ##STR1483## ##STR1484##  ##STR1485## ##STR1486##  2.11 451.2987 452.3647  490 ##STR1487## ##STR1488## 
##STR1489## ##STR1490##  2.09 437.2831 438.3419  491 ##STR1491## ##STR1492##  ##STR1493## ##STR1494##  2.14 487.2987 488.3654  492 ##STR1495## ##STR1496##  ##STR1497## ##STR1498##  2.07 481.2729 482.3416  493 ##STR1499## ##STR1500##  ##STR1501##
##STR1502##  2.1 451.2987 452.3654  494 ##STR1503## ##STR1504##  ##STR1505## ##STR1506##  2.09 437.2831 438.3447  495 ##STR1507## ##STR1508##  ##STR1509## ##STR1510##  2.14 487.2987 488.3656  496 ##STR1511## ##STR1512##  ##STR1513## ##STR1514##  2.07
481.2729 482.3421  497 ##STR1515## ##STR1516##  ##STR1517## ##STR1518##  2.02 453.278 454.3456  498 ##STR1519## ##STR1520##  ##STR1521## ##STR1522##  2.01 439.2624 440.3276  499 ##STR1523## ##STR1524##  ##STR1525## ##STR1526##  2.06 489.278 490.3461  500
##STR1527## ##STR1528##  ##STR1529## ##STR1530##  1.99 483.2522 484.3252  501 ##STR1531## ##STR1532##  ##STR1533## ##STR1534##  2 453.278 454.3479  502 ##STR1535## ##STR1536##  ##STR1537## ##STR1538##  1.99 439.2624 440.332  503 ##STR1539## ##STR1540## 
##STR1541## ##STR1542##  2.06 489.278 490.3477  504 ##STR1543## ##STR1544##  ##STR1545## ##STR1546##  1.97 483.2522 484.3253  505 ##STR1547## ##STR1548##


 ##STR1549## ##STR1550##  1.96 453.278 454.3445  506 ##STR1551## ##STR1552##  ##STR1553## ##STR1554##  1.99 439.2624 440.3253  507 ##STR1555## ##STR1556##  ##STR1557## ##STR1558##  2.07 489.278 490.3457  508 ##STR1559## ##STR1560##  ##STR1561##
##STR1562##  1.97 483.2522 484.3227  509 ##STR1563## ##STR1564##  ##STR1565## ##STR1566##  2.07 455.2737 456.3386  510 ##STR1567## ##STR1568##  ##STR1569## ##STR1570##  2.06 441.258 442.3267  511 ##STR1571## ##STR1572##  ##STR1573## ##STR1574##  2.11
491.2737 492.3441  512 ##STR1575## ##STR1576##  ##STR1577## ##STR1578##  2.04 485.2479 486.3185  513 ##STR1579## ##STR1580##  ##STR1581## ##STR1582##  2.04 441.258 442.3253  514 ##STR1583## ##STR1584##  ##STR1585## ##STR1586##  2.03 485.2479 486.3174 
515 ##STR1587## ##STR1588##  ##STR1589## ##STR1590##  2.05 455.2737 456.3376  516 ##STR1591## ##STR1592##  ##STR1593## ##STR1594##  2.04 441.258 442.325  517 ##STR1595## ##STR1596##  ##STR1597## ##STR1598##  2.1 491.2737 492.3412  518 ##STR1599##
##STR1600##  ##STR1601## ##STR1602##  2.02 485.2479 486.3193  519 ##STR1603## ##STR1604##  ##STR1605## ##STR1606##  2.04 487.2027 488.2782  520 ##STR1607## ##STR1608##  ##STR1609## ##STR1610##  2.12 493.2285 494.3027  521 ##STR1611## ##STR1612## 
##STR1613## ##STR1614##  2.04 487.2027 488.2797  522 ##STR1615## ##STR1616##  ##STR1617## ##STR1618##  2.06 457.2285 458.2941  523 ##STR1619## ##STR1620##  ##STR1621## ##STR1622##  2.04 443.2128 444.2792  524 ##STR1623## ##STR1624##  ##STR1625##
##STR1626##  2.09 493.2285 494.3003  525 ##STR1627## ##STR1628##  ##STR1629## ##STR1630##  2.03 487.2027 488.278  526 ##STR1631## ##STR1632##  ##STR1633## ##STR1634##  2 489.2228 490.2792  527 ##STR1635## ##STR1636##  ##STR1637## ##STR1638##  2.02
445.2329 446.2807  528 ##STR1639## ##STR1640##  ##STR1641## ##STR1642##  2.06 495.2486 496.2982  529 ##STR1643## ##STR1644##  ##STR1645## ##STR1646##  2 489.2228 490.2744  530 ##STR1647## ##STR1648##  ##STR1649## ##STR1650##  2.01 445.2329 446.282  531
##STR1651## ##STR1652##  ##STR1653## ##STR1654##  2.07 495.2486 496.2984  532 ##STR1655## ##STR1656##  ##STR1657## ##STR1658##  1.99 489.2228 490.2794  533 ##STR1659## ##STR1660##  ##STR1661## ##STR1662##  2.08 495.2486 496.3038  534 ##STR1663##
##STR1664##  ##STR1665## ##STR1666##  2 489.2228 490.2825  535 ##STR1667## ##STR1668##  ##STR1669## ##STR1670##  2.14 465.3144 466.3682  536 ##STR1671## ##STR1672##  ##STR1673## ##STR1674##  2.13 451.2987 452.3522  537 ##STR1675## ##STR1676## 
##STR1677## ##STR1678##  2.19 501.3144 502.3722  538 ##STR1679## ##STR1680##  ##STR1681## ##STR1682##  2.11 495.2886 496.3486  539 ##STR1683## ##STR1684##  ##STR1685## ##STR1686##  2.12 451.2987 452.3553  540 ##STR1687## ##STR1688##  ##STR1689##
##STR1690##  2.16 501.3144 502.3736  541 ##STR1691## ##STR1692##  ##STR1693## ##STR1694##  2.1 495.2886 496.3533  542 ##STR1695## ##STR1696##  ##STR1697## ##STR1698##  2.05 467.2937 468.352  543 ##STR1699## ##STR1700##  ##STR1701## ##STR1702##  2.04
453.278 454.334  544 ##STR1703## ##STR1704##  ##STR1705## ##STR1706##  2.1 503.2937 504.355  545 ##STR1707## ##STR1708##  ##STR1709## ##STR1710##  2.02 497.2679 498.3338  546 ##STR1711## ##STR1712##  ##STR1713## ##STR1714##  2.1 503.2937 504.3604  547
##STR1715## ##STR1716##  ##STR1717## ##STR1718##  2.01 497.2679 498.336  548 ##STR1719## ##STR1720##  ##STR1721## ##STR1722##  2.02 467.2937 468.3528  549 ##STR1723## ##STR1724##  ##STR1725## ##STR1726##  2.01 497.2679 498.3345  550 ##STR1727##
##STR1728##  ##STR1729## ##STR1730##  1.99 467.2573 468.3251  551 ##STR1731## ##STR1732##  ##STR1733## ##STR1734##  2.05 503.2573 504.3299  552 ##STR1735## ##STR1736##  ##STR1737## ##STR1738##  1.97 497.2314 498.303  553 ##STR1739## ##STR1740## 
##STR1741## ##STR1742##  2.05 469.2552 470.3185  554 ##STR1743## ##STR1744##  ##STR1745## ##STR1746##  2.05 455.2395 456.3164  555 ##STR1747## ##STR1748##  ##STR1749## ##STR1750##  2.1 505.2552 506.3273  556 ##STR1751## ##STR1752##  ##STR1753##
##STR1754##  2.03 499.2293 500.3005  557 ##STR1755## ##STR1756##  ##STR1757## ##STR1758##  1.99 471.2686 472.3348  558 ##STR1759## ##STR1760##  ##STR1761## ##STR1762##  1.98 457.2529 458.3177  559 ##STR1763## ##STR1764##  ##STR1765## ##STR1766##  2.05
507.2686 508.3424  560 ##STR1767## ##STR1768##  ##STR1769## ##STR1770##  1.96 501.2428 502.3192  561 ##STR1771## ##STR1772##  ##STR1773## ##STR1774##  2.1 457.2285 458.2933  562 ##STR1775## ##STR1776##  ##STR1777## ##STR1778##  2.14 507.2441 508.3201 
563 ##STR1779## ##STR1780##  ##STR1781## ##STR1782##  2.08 501.2183 502.2952  564 ##STR1783## ##STR1784##  ##STR1785## ##STR1786##  2.04 505.1932 506.2737  565 ##STR1787## ##STR1788##  ##STR1789## ##STR1790##  2.17 465.3144 466.3809  566 ##STR1791##
##STR1792##  ##STR1793## ##STR1794##  2.15 509.3042 510.3789  567 ##STR1795## ##STR1796##  ##STR1797## ##STR1798##  2.15 479.33 480.3981  568 ##STR1799## ##STR1800##  ##STR1801## ##STR1802##  2.14 465.3144 466.3795  569 ##STR1803## ##STR1804## 
##STR1805## ##STR1806##  2.13 509.3042 510.383  570 ##STR1807## ##STR1808##  ##STR1809## ##STR1810##  2.06 511.2835 512.3632  571 ##STR1811## ##STR1812##  ##STR1813## ##STR1814##  2.06 467.2937 468.3609  572 ##STR1815## ##STR1816##  ##STR1817##
##STR1818##  2.12 517.3093 518.3871  573 ##STR1819## ##STR1820##  ##STR1821## ##STR1822##  2.04 511.2835 512.3613  574 ##STR1823## ##STR1824##  ##STR1825## ##STR1826##  2.1 483.2708 484.3423  575 ##STR1827## ##STR1828##  ##STR1829## ##STR1830##  2.08
469.2552 470.3222  576 ##STR1831## ##STR1832##  ##STR1833## ##STR1834##  2.13 519.2708 520.3477  577 ##STR1835## ##STR1836##  ##STR1837## ##STR1838##  2.06 513.245 514.3214  578 ##STR1839## ##STR1840##  ##STR1841## ##STR1842##  2.02 481.2141 482.2788 
579 ##STR1843## ##STR1844##  ##STR1845## ##STR1846##  2 525.2039 526.2794  580 ##STR1847## ##STR1848##  ##STR1849## ##STR1850##  2.08 513.2392 514.3017  581 ##STR1851## ##STR1852##  ##STR1853## ##STR1854##  2 507.2133 508.2841  582 ##STR1855##
##STR1856##  ##STR1857## ##STR1858##  2.06 513.2392 514.3171  583 ##STR1859## ##STR1860##  ##STR1861## ##STR1862##  1.98 507.2133 508.2843  584 ##STR1863## ##STR1864##  ##STR1865## ##STR1866##  2.03 461.2034 462.2718  585 ##STR1867## ##STR1868## 
##STR1869## ##STR1870##  2.08 611.2101 612.2986  586 ##STR1871## ##STR1872##  ##STR1873## ##STR1874##  2.01 505.1932 506.2769  587 ##STR1875## ##STR1876##  ##STR1877## ##STR1878##  2.17 561.1505 562.2524  588 ##STR1879## ##STR1880##  ##STR1881##
##STR1882##  1.99 527.2784 528.3599


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##STR1895## ##STR1896##  ##STR1897## ##STR1898##  2.03 513.245 514.321  593 ##STR1899## ##STR1900##  ##STR1901## ##STR1902##  2 467.2573 468.3217  594 ##STR1903## ##STR1904##  ##STR1905## ##STR1906##  1.97 511.2471 512.3246  595 ##STR1907## ##STR1908## 
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##STR2831## ##STR2832##  ##STR2833## ##STR2834##  1.97 473.2654 474.3578  827 ##STR2835## ##STR2836##  ##STR2837## ##STR2838##  2.08 499.281 500.3929  828 ##STR2839## ##STR2840##  ##STR2841## ##STR2842##  829 ##STR2843## ##STR2844##  ##STR2845##
##STR2846##  2.08 577.274 578.3961  830 ##STR2847## ##STR2848##  ##STR2849## ##STR2850##  2 503.2384 504.3399  831 ##STR2851## ##STR2852##  ##STR2853## ##STR2854##  1.99 515.2584 516.3593  832 ##STR2855## ##STR2856##  ##STR2857## ##STR2858##  2.03
529.274 530.3805  833 ##STR2859## ##STR2860##  ##STR2861## ##STR2862##  2.03 563.1584 564.2842  834 ##STR2863## ##STR2864##  ##STR2865## ##STR2866##  1.98 545.269 546.3808  835 ##STR2867## ##STR2868##  ##STR2869## ##STR2870##  1.97 545.269 546.374  836
##STR2871## ##STR2872##  ##STR2873## ##STR2874##  1.98 545.269 546.3859  837 ##STR2875## ##STR2876##  ##STR2877## ##STR2878##  1.92 545.269 546.3798  838 ##STR2879## ##STR2880##  ##STR2881## ##STR2882##  1.96 559.2846 560.3983  839 ##STR2883##
##STR2884##  ##STR2885## ##STR2886##  2.05 535.2635 536.3757  840 ##STR2887## ##STR2888##  ##STR2889## ##STR2890##  2.04 592.285 593.4103  841 ##STR2891## ##STR2892##  ##STR2893## ##STR2894##  842 ##STR2895## ##STR2896##  ##STR2897## ##STR2898##  2.01
544.2308 545.3511  843 ##STR2899## ##STR2900##  ##STR2901## ##STR2902##  1.88 547.2026 548.3105  844 ##STR2903## ##STR2904##  ##STR2905## ##STR2906##  1.9 549.2228 550.3254  845 ##STR2907## ##STR2908##  ##STR2909## ##STR2910##  1.97 525.2592 526.3528 
846 ##STR2911## ##STR2912##  ##STR2913## ##STR2914##  1.94 577.2132 578.3243  847 ##STR2915## ##STR2916##  ##STR2917## ##STR2918##  2.01 553.2496 554.3531  848 ##STR2919## ##STR2920##  ##STR2921## ##STR2922##  1.92 581.229 582.3329  849 ##STR2923##
##STR2924##  ##STR2925## ##STR2926##  1.95 551.1531 552.2697  850 ##STR2927## ##STR2928##  ##STR2929## ##STR2930##  1.95 581.1637 582.2848  851 ##STR2931## ##STR2932##  ##STR2933## ##STR2934##  2.03 557.2001 558.311  852 ##STR2935## ##STR2936## 
##STR2937## ##STR2938##  1.9 591.1522 592.27


 853 ##STR2939## ##STR2940##  ##STR2941## ##STR2942##  2.02 617.3042 618.4236  854 ##STR2943## ##STR2944##  ##STR2945## ##STR2946##  1.92 639.1383 640.2621  855 ##STR2947## ##STR2948##  ##STR2949## ##STR2950##  1.95 607.2238 608.3556  856
##STR2951## ##STR2952##  ##STR2953## ##STR2954##  1.92 621.1627 622.29  857 ##STR2955## ##STR2956##  ##STR2957## ##STR2958##  1.96 651.1733 652.31  858 ##STR2959## ##STR2960##  ##STR2961## ##STR2962##  1.93 657.1288 658.2678  859 ##STR2963## ##STR2964## 
##STR2965## ##STR2966##  1.95 605.1678 606.29  860 ##STR2967## ##STR2968##  ##STR2969## ##STR2970##  2.02 581.2042 582.32  861 ##STR2971## ##STR2972##  ##STR2973## ##STR2974##  1.96 593.1904 594.3127  862 ##STR2975## ##STR2976##  ##STR2977## ##STR2978## 
1.97 615.1901 616.3185  863 ##STR2979## ##STR2980##  ##STR2981## ##STR2982##  2.04 591.2264 592.3466  864 ##STR2983## ##STR2984##  ##STR2985## ##STR2986##  1.93 578.2682 579.3848


 TABLE 2  ##STR2987##  H +  CMP  Rtn. Cmd. Ion  # R1 R2 R3  R4 R5 R6  Time Mass Obs  900 ##STR2988## ##STR2989##  ##STR2990## ##STR2991##  ##STR2992## 1.99 453.1779 456.2343  901 ##STR2993## ##STR2994##  ##STR2995## ##STR2996##  ##STR2997##  902
##STR2998## ##STR2999##  ##STR3000## ##STR3001##  ##STR3002## 1.96 409.2285 410.2904  903 ##STR3003## ##STR3004##  ##STR3005## ##STR3006##  ##STR3007## 1.98 451.2987 452.3564  904 ##STR3008## ##STR3009##  ##STR3010## ##STR3011##  ##STR3012## 1.91
389.2831 390.327  905 ##STR3013## ##STR3014##  ##STR3015## ##STR3016##  ##STR3017## 2.06 515.2703 516.3389  906 ##STR3018## ##STR3019##  ##STR3020## ##STR3021##  ##STR3022## 2.02 501.2547 502.3203  907 ##STR3023## ##STR3024##  ##STR3025## ##STR3026## 
##STR3027## 2.05 535.239 536.3062  908 ##STR3028## ##STR3029##  ##STR3030## ##STR3031##  ##STR3032## 1.95 495.2886 496.338  909 ##STR3033## ##STR3034##  ##STR3035## ##STR3036##  ##STR3037## 1.95 509.3042 510.349  910 ##STR3038## ##STR3039##  ##STR3040##
##STR3041##  ##STR3042## 2.06 543.2886 544.3537  911 ##STR3043## ##STR3044##  ##STR3045## ##STR3046##  ##STR3047## 2.06 529.2729 530.3288  912 ##STR3048## ##STR3049##  ##STR3050## ##STR3051##  ##STR3052## 2.06 527.2936 528.3539  913 ##STR3053##
##STR3054##  ##STR3055## ##STR3056##  ##STR3057## 1.91 493.3093 494.3662  914 ##STR3058## ##STR3059##  ##STR3060## ##STR3061##  ##STR3062## 1.98 501.278 502.3292  915 ##STR3063## ##STR3064##  ##STR3065## ##STR3066##  ##STR3067## 2.04 481.286 482.3375 
916 ##STR3068## ##STR3069##  ##STR3070## ##STR3071##  ##STR3072## 2.06 509.3042 510.3504  917 ##STR3073## ##STR3074##  ##STR3075## ##STR3076##  ##STR3077## 2.04 533.2941 544.3566  918 ##STR3078## ##STR3079##  ##STR3080## ##STR3081##  ##STR3082## 2.01
599.2602 560.3214  919 ##STR3083## ##STR3084##  ##STR3085## ##STR3086##  ##STR3087## 1.98 599.2602 560.3226  920 ##STR3088## ##STR3089##  ##STR3090## ##STR3091##  ##STR3092## 2.07 515.2936 516.3561  921 ##STR3093## ##STR3094##  ##STR3095## ##STR3096## 
##STR3097## 1.8 467.2937 466.3449  922 ##STR3098## ##STR3099##  ##STR3100## ##STR3101##  ##STR3102## 1.97 486.255 487.3133  923 ##STR3103## ##STR3104##  ##STR3105## ##STR3106##  ##STR3107## 1.96 520.2394 521.3087  924 ##STR3108## ##STR3109##  ##STR3110##
##STR3111##  ##STR3112## 1.77 521.3519 522.4169  925 ##STR3113## ##STR3114##  ##STR3115## ##STR3116##  ##STR3117## 1.79 555.3362 566.421  926 ##STR3118## ##STR3119##  ##STR3120## ##STR3121##  ##STR3122## 2.06 565.2496 566.3239  927 ##STR3123##
##STR3124##  ##STR3125## ##STR3126##  ##STR3127## 1.76 545.3155 546.3849  928 ##STR3128## ##STR3129##  ##STR3130## ##STR3131##  ##STR3132## 2.02 531.2563 532.3318  929 ##STR3133## ##STR3134##  ##STR3135## ##STR3136##  ##STR3137## 1.79 497.3042 498.3625 
930 ##STR3138## ##STR3139##  ##STR3140## ##STR3141##  ##STR3142## 1.95 525.2991 526.3686  931 ##STR3143## ##STR3144##  ##STR3145## ##STR3146##  ##STR3147## 1.74 511.3311 512.3882  932 ##STR3148## ##STR3149##  ##STR3150## ##STR3151##  ##STR3152## 2
531.2886 532.3475  933 ##STR3153## ##STR3154##  ##STR3155## ##STR3156##  ##STR3157## 2 469.2893 470.3573  934 ##STR3158## ##STR3159##  ##STR3160## ##STR3161##  ##STR3162## 2.03 519.2452 520.3179  935 ##STR3163## ##STR3164##  ##STR3165## ##STR3166## 
##STR3167## 2.05 553.2296 554.3043  936 ##STR3168## ##STR3169##  ##STR3170## ##STR3171##  ##STR3172## 1.97 513.2792 514.3508  937 ##STR3173## ##STR3174##  ##STR3175## ##STR3176##  ##STR3177## 2.06 547.2635 548.3326  938 ##STR3178## ##STR3179## 
##STR3180## ##STR3181##  ##STR3182## 1.71 483.2886 484.3469  939 ##STR3183## ##STR3184##  ##STR3185## ##STR3186##  ##STR3187## 1.86 423.2675 424.3207  940 ##STR3188## ##STR3189##  ##STR3190## ##STR3191##  ##STR3192## 1.94 458.2504 459.2958  941
##STR3193## ##STR3194##  ##STR3195## ##STR3196##  ##STR3197## 1.93 492.2378 493.2848  942 ##STR3198## ##STR3199##  ##STR3200## ##STR3201##  ##STR3202## 1.74 437.3049 466.3629  943 ##STR3203## ##STR3204##  ##STR3205## ##STR3206##  ##STR3207## 1.92
437.2831 438.2847  944 ##STR3208## ##STR3209##  ##STR3210## ##STR3211##  ##STR3212## 1.77 495.3362 496.4057  945 ##STR3213## ##STR3214##  ##STR3215## ##STR3216##  ##STR3217## 1.74 481.3206 482.3854  946 ##STR3218## ##STR3219##  ##STR3220## ##STR3221## 
##STR3222## 1.76 525.3467 526.4145  947 ##STR3223## ##STR3224##  ##STR3225## ##STR3226##  ##STR3227## 1.98 481.2729 482.3188  948 ##STR3228## ##STR3229##  ##STR3230## ##STR3231##  ##STR3232## 2.01 501.278 502.3374  949 ##STR3233## ##STR3234## 
##STR3235## ##STR3236##  ##STR3237## 1.99 501.278 502.3323  950 ##STR3238## ##STR3239##  ##STR3240## ##STR3241##  ##STR3242## 1.88 467.2937 468.3544  951 ##STR3243## ##STR3244##  ##STR3245## ##STR3246##  ##STR3247## 1.88 467.2937 468.352  952 ##STR3248##
##STR3249##  ##STR3250## ##STR3251##  ##STR3252## 2.04 543.2886 544.3618  953 ##STR3253## ##STR3254##  ##STR3255## ##STR3256##  ##STR3257## 2.03 509.3042 510.364  954 ##STR3258## ##STR3259##  ##STR3260## ##STR3261##  ##STR3262## 1.93 536.294 537.3635 
955 ##STR3263## ##STR3264##  ##STR3265## ##STR3266##  ##STR3267## 1.94 502.3097 503.3694  956 ##STR3268## ##STR3269##  ##STR3270## ##STR3271##  ##STR3272## 2.05 542.3409 543.4108  957 ##STR3273## ##STR3274##  ##STR3275## ##STR3276##  ##STR3277## 1.92
481.3093 482.3674  958 ##STR3278## ##STR3279##  ##STR3280## ##STR3281##  ##STR3282## 1.99 529.2729 530.3309  959 ##STR3283## ##STR3284##  ##STR3285## ##STR3286##  ##STR3287## 1.97 495.2886 496.3324  960 ##STR3288## ##STR3289##  ##STR3290## ##STR3291## 
##STR3292## 2.08 535.3199 536.3663  961 ##STR3293## ##STR3294##  ##STR3295## ##STR3296##  ##STR3297## 1.93 502.3097 503.3532  962 ##STR3298## ##STR3299##  ##STR3300## ##STR3301##  ##STR3302## 2.06 542.3409 543.387  963 ##STR3303## ##STR3304## 
##STR3305## ##STR3306##  ##STR3307## 1.77 559.3311 560.4  964 ##STR3308## ##STR3309##  ##STR3310## ##STR3311##  ##STR3312## 1.77 529.3206 530.373  965 ##STR3313## ##STR3314##  ##STR3315## ##STR3316##  ##STR3317##  966 ##STR3318## ##STR3319##  ##STR3320##
##STR3321##  ##STR3322## 1.94 528.3253 529.3721  967 ##STR3323## ##STR3324##  ##STR3325## ##STR3326##  ##STR3327## 1.88 494.3409 495.3921  968 ##STR3328## ##STR3329##  ##STR3330## ##STR3331##  ##STR3332## 2.05 534.3723 535.461  969 ##STR3333##
##STR3334##  ##STR3335## ##STR3336##  ##STR3337## 1.77 491.3049 492.3542  970 ##STR3338## ##STR3339##  ##STR3340## ##STR3341##  ##STR3342## 2.03 568.2661 569.3215  971 ##STR3343## ##STR3344##  ##STR3345## ##STR3346##  ##STR3347## 1.98 534.2817 535.3365 
972 ##STR3348## ##STR3349##  ##STR3350## ##STR3351##  ##STR3352## 2.14 574.313 575.38  973 ##STR3353## ##STR3354##  ##STR3355## ##STR3356##  ##STR3357## 1.94 542.3049 543.3302  974 ##STR3358## ##STR3359##  ##STR3360## ##STR3361##  ##STR3362## 1.89
507.3202 509.3457  975 ##STR3363## ##STR3364##  ##STR3365## ##STR3366##  ##STR3367## 1.91 522.3359 523.3574  976 ##STR3368## ##STR3369##  ##STR3370## ##STR3371##  ##STR3372## 2.03 562.3672 563.3868  977 ##STR3373## ##STR3374##  ##STR3375## ##STR3376## 
##STR3377## 1.96 515.2936 516.3203  978 ##STR3378## ##STR3379##  ##STR3380## ##STR3381##  ##STR3382## 1.86 481.3093 482.3423  979 ##STR3383## ##STR3384##


 ##STR3385## ##STR3386##  ##STR3387## 2.05 521.3406 522.3415  980 ##STR3388## ##STR3389##  ##STR3390## ##STR3391##  ##STR3392## 2.06 515.2936 516.3033  981 ##STR3393## ##STR3394##  ##STR3395## ##STR3396##  ##STR3397## 1.89 481.3093 482.3204  982
##STR3398## ##STR3399##  ##STR3400## ##STR3401##  ##STR3402## 2.12 521.3406 522.3559  983 ##STR3403## ##STR3404##  ##STR3405## ##STR3406##  ##STR3407## 2.06 515.2936 516.3141  984 ##STR3408## ##STR3409##  ##STR3410## ##STR3411##  ##STR3412## 1.99
481.3093 482.3264  985 ##STR3413## ##STR3414##  ##STR3415## ##STR3416##  ##STR3417## 2.15 521.3406 522.3597  986 ##STR3418## ##STR3419##  ##STR3420## ##STR3421##  ##STR3422## 2.03 489.3355 490.3545  987 ##STR3423## ##STR3424##  ##STR3425## ##STR3426## 
##STR3427## 1.93 461.3406 462.3651  988 ##STR3428## ##STR3429##  ##STR3430## ##STR3431##  ##STR3432## 2.1 549.3355 550.3556  989 ##STR3433## ##STR3434##  ##STR3435## ##STR3436##  ##STR3437## 1.99 559.2835 560.3169  990 ##STR3438## ##STR3439## 
##STR3440## ##STR3441##  ##STR3442## 2.06 565.3304 566.3608  991 ##STR3443## ##STR3444##  ##STR3445## ##STR3446##  ##STR3447## 1.98 545.3042 546.332  992 ##STR3448## ##STR3449##  ##STR3450## ##STR3451##  ##STR3452## 1.82 511.3199 512.3492  993
##STR3453## ##STR3454##  ##STR3455## ##STR3456##  ##STR3457## 2.05 551.3512 552.3806  994 ##STR3458## ##STR3459##  ##STR3460## ##STR3461##  ##STR3462## 1.91 488.3515 489.3748  995 ##STR3463## ##STR3464##  ##STR3465## ##STR3466##  ##STR3467## 2.02
546.2631 547.2886  996 ##STR3468## ##STR3469##  ##STR3470## ##STR3471##  ##STR3472## 2 512.2787 513.3031  997 ##STR3473## ##STR3474##  ##STR3475## ##STR3476##  ##STR3477## 2.11 522.3101 553.335  998 ##STR3478## ##STR3479##  ##STR3480## ##STR3481## 
##STR3482## 2.02 546.2631 547.2888  999 ##STR3483## ##STR3484##  ##STR3485## ##STR3486##  ##STR3487## 2.03 512.2787 513.3018  1000 ##STR3488## ##STR3489##  ##STR3490## ##STR3491##  ##STR3492## 2.11 552.3101 553.3454  1001 ##STR3493## ##STR3494## 
##STR3495## ##STR3496##  ##STR3497## 2.06 578.4349 579.501  1002 ##STR3498## ##STR3499##  ##STR3500## ##STR3501##  ##STR3502## 2.14 318.4661 619.54  1003 ##STR3503## ##STR3504##  ##STR3505## ##STR3506##  ##STR3507## 1.71 552.3828 553.43  1004 ##STR3508##
##STR3509##  ##STR3510## ##STR3511##  ##STR3512## 1.92 592.4141 593.47  1005 ##STR3513## ##STR3514##  ##STR3515## ##STR3516##  ##STR3517## 1.9 474.3359 475.3617  1006 ##STR3518## ##STR3519##  ##STR3520## ##STR3521##  ##STR3522## 1.81 558.2995 559.3615 
1007 ##STR3523## ##STR3524##  ##STR3525## ##STR3526##  ##STR3527## 1.78 460.3566 461.4005  1008 ##STR3528## ##STR3529##  ##STR3530## ##STR3531##  ##STR3532## 2.03 543.2886 544.3141  1009 ##STR3533## ##STR3534##  ##STR3535## ##STR3536##  ##STR3537## 1.95
509.3042 510.3276  1010 ##STR3538## ##STR3539##  ##STR3540## ##STR3541##  ##STR3542## 2.08 549.3355 550.3668  1011 ##STR3543## ##STR3544##  ##STR3545## ##STR3546##  ##STR3547## 1.96 515.2936 516.3184  1012 ##STR3548## ##STR3549##  ##STR3550## ##STR3551## ##STR3552## 1.84 481.3093 482.3309  1013 ##STR3553## ##STR3554##  ##STR3555## ##STR3556##  ##STR3557## 1.98 521.3406 522.3765  1014 ##STR3558## ##STR3559##  ##STR3560## ##STR3561##  ##STR3562## 1.88 564.2559 565.3013  1015 ##STR3563## ##STR3564## 
##STR3565## ##STR3566##  ##STR3567## 1.87 530.2715 531.3078  1016 ##STR3568## ##STR3569##  ##STR3570## ##STR3571##  ##STR3572## 1.88 511.3199 512.3484  1017 ##STR3573## ##STR3574##  ##STR3575## ##STR3576##  ##STR3577## 1.98 547.301 548.3231  1018
##STR3578## ##STR3579##  ##STR3580## ##STR3581##  ##STR3582## 1.96 523.3199 524.3481  1019 ##STR3583## ##STR3584##  ##STR3585## ##STR3586##  ##STR3587## 1.82 489.3355 490.3575  1020 ##STR3588## ##STR3589##  ##STR3590## ##STR3591##  ##STR3592## 1.9
509.3042 510.3383  1021 ##STR3593## ##STR3594##  ##STR3595## ##STR3596##  ##STR3597## 1.88 495.325 496.3488  1022 ##STR3598## ##STR3599##  ##STR3600## ##STR3601##  ##STR3602## 1.77 461.3406 462.3634  1023 ##STR3603## ##STR3604##  ##STR3605## ##STR3606## 
##STR3607## 2.03 573.2628 574.2927  1024 ##STR3608## ##STR3609##  ##STR3610## ##STR3611##  ##STR3612## 2.03 587.2784 588.3088  1025 ##STR3613## ##STR3614##  ##STR3615## ##STR3616##  ##STR3617## 1.96 573.2628 574.3035  1026 ##STR3618## ##STR3619## 
##STR3620## ##STR3621##  ##STR3622##  1027 ##STR3623## ##STR3624##  ##STR3625## ##STR3626##  ##STR3627## 1.85 544.2872 545.3313  1028 ##STR3628## ##STR3629##  ##STR3630## ##STR3631##  ##STR3632## 2.03 543.2886 544.3122  1029 ##STR3633## ##STR3634## 
##STR3635## ##STR3636##  ##STR3637## 2.03 509.3042 510.3173  1030 ##STR3638## ##STR3639##  ##STR3640## ##STR3641##  ##STR3642## 2.12 549.3355 550.3542  1031 ##STR3643## ##STR3644##  ##STR3645## ##STR3646##  ##STR3647## 1.98 529.2729 530.2999  1032
##STR3648## ##STR3649##  ##STR3650## ##STR3651##  ##STR3652## 2.08 535.3199 536.3453  1033 ##STR3653## ##STR3654##  ##STR3655## ##STR3656##  ##STR3657## 1.97 515.2936 516.3203  1034 ##STR3658## ##STR3659##  ##STR3660## ##STR3661##  ##STR3662## 1.87
481.3093 482.3294  1035 ##STR3663## ##STR3664##  ##STR3665## ##STR3666##  ##STR3667## 2.06 559.2835 560.311  1036 ##STR3668## ##STR3669##  ##STR3670## ##STR3671##  ##STR3672## 2.03 525.2991 526.3195  1037 ##STR3673## ##STR3674##  ##STR3675## ##STR3676## 
##STR3677## 2.17 565.3304 566.35  1038 ##STR3678## ##STR3679##  ##STR3680## ##STR3681##  ##STR3682##  1039 ##STR3683## ##STR3684##  ##STR3685## ##STR3686##  ##STR3687## 2.12 551.3148 552.3455  1040 ##STR3688## ##STR3689##  ##STR3690## ##STR3691## 
##STR3692## 1.93 531.2886 532.3281  1041 ##STR3693## ##STR3694##  ##STR3695## ##STR3696##  ##STR3697## 1.74 497.3042 498.3471  1042 ##STR3698## ##STR3699##  ##STR3700## ##STR3701##  ##STR3702## 1.99 537.3355 538.3746  1043 ##STR3703## ##STR3704## 
##STR3705## ##STR3706##  ##STR3707## 1.91 572.2787 573.3109  1044 ##STR3708## ##STR3709##  ##STR3710## ##STR3711##  ##STR3712## 1.88 494.3046 495.3434  1045 ##STR3713## ##STR3714##  ##STR3715## ##STR3716##  ##STR3717## 1.91 572.2821 573.3249  1046
##STR3718## ##STR3719##  ##STR3720## ##STR3721## ##STR3722##  ##STR3723##  1047 ##STR3724## ##STR3725##  ##STR3726## ##STR3727## ##STR3728##  ##STR3729##  1048 ##STR3730## ##STR3731##  ##STR3732## ##STR3733##  ##STR3734## 2.04 595.2777 596.3219  1049
##STR3735## ##STR3736##  ##STR3737## ##STR3738##  ##STR3739## 1.85 588.3231 589.3849  1050 ##STR3740## ##STR3741##  ##STR3742## ##STR3743##  ##STR3744## 1.72 554.3621 555.4208  1051 ##STR3745## ##STR3746##  ##STR3747## ##STR3748##  ##STR3749## 2 547.301
548.3278  1052 ##STR3750## ##STR3751##  ##STR3752## ##STR3753##  ##STR3754## 1.78 582.357 583.4136  1053 ##STR3755## ##STR3756##  ##STR3757## ##STR3758##  ##STR3759## 1.99 573.2991 574.3322  1054 ##STR3760## ##STR3761##  ##STR3762## ##STR3763## 
##STR3764## 1.95 539.3148 540.3422  1055 ##STR3765## ##STR3766##  ##STR3767## ##STR3768##  ##STR3769## 2.1 579.3461 580.3743  1056 ##STR3770## ##STR3771##  ##STR3772## ##STR3773##  ##STR3774## 1.97 545.3042 546.3319  1057 ##STR3775## ##STR3776## 
##STR3777## ##STR3778##  ##STR3779## 1.81 511.3199 512.3505  1058 ##STR3780## ##STR3781##  ##STR3782## ##STR3783##  ##STR3784## 2.04 551.3512 552.3825  1059 ##STR3785## ##STR3786##  ##STR3787## ##STR3788##  ##STR3789## 1.93 606.2665 607.3164  1060
##STR3790## ##STR3791##  ##STR3792## ##STR3793##  ##STR3794## 1.91 528.2889 529.3276  1061 ##STR3795## ##STR3796##  ##STR3797## ##STR3798##  ##STR3799##  1062 ##STR3800## ##STR3801##  ##STR3802## ##STR3803##  ##STR3804## 1.98 527.2971 528.3281


 1063 ##STR3805## ##STR3806##  ##STR3807## ##STR3808##  ##STR3809## 2.09 561.2814 562.3166  1064 ##STR3810## ##STR3811##  ##STR3812## ##STR3813##  ##STR3814## 1.87 608.2457 609.2976  1065 ##STR3815## ##STR3816##  ##STR3817## ##STR3818## 
##STR3819##  1066 ##STR3820## ##STR3821##  ##STR3822## ##STR3823##  ##STR3824## 1.9 572.2821 573.3206  1067 ##STR3825## ##STR3826##  ##STR3827## ##STR3828##  ##STR3829## 1.79 580.2508 581.3011  1068 ##STR3830## ##STR3831##  ##STR3832## ##STR3833## 
##STR3834## 1.9 650.2563 651.3043  1069 ##STR3835## ##STR3836##  ##STR3837## ##STR3838##  ##STR3839## 1.92 606.2665 607.2383  1070 ##STR3840## ##STR3841##  ##STR3842## ##STR3843##  ##STR3844## 1.9 650.2563 651.2313  1071 ##STR3845## ##STR3846## 
##STR3847## ##STR3848##  ##STR3849## 1.96 520.2838 521.3221  1072 ##STR3850## ##STR3851##  ##STR3852## ##STR3853##  ##STR3854## 1.88 602.2927 603.3342  1073 ##STR3855## ##STR3856##  ##STR3857## ##STR3858##  ##STR3859## 1.93 631.3192 632.3643  1074
##STR3860## ##STR3861##  ##STR3862## ##STR3863##  ##STR3864## 1.78 552.3464 553.3979  1075 ##STR3865## ##STR3866##  ##STR3867## ##STR3868##  ##STR3869## 1.9 582.3206 583.3616  1076 ##STR3870## ##STR3871##  ##STR3872## ##STR3873##  ##STR3874## 1.95
534.2995 535.3354  1077 ##STR3875## ##STR3876##  ##STR3877## ##STR3878##  ##STR3879## 1.99 571.3311 572.3079  1078 ##STR3880## ##STR3881##  ##STR3882## ##STR3883##  ##STR3884## 1.75 574.2978 575.2848  1079 ##STR3885## ##STR3886##  ##STR3887## ##STR3888## ##STR3889## 1.97 614.329 615.3132  1080 ##STR3890## ##STR3891##  ##STR3892## ##STR3893## ##STR3894##  ##STR3895## 1.97 587.2784 588.2736  1081 ##STR3896## ##STR3897##  ##STR3898## ##STR3899##  ##STR3900## 1.78 608.2457 609.2491  1082 ##STR3901##
##STR3902##  ##STR3903## ##STR3904##  ##STR3905## 2.03 531.2653 532.2452  1083 ##STR3906## ##STR3907##  ##STR3908## ##STR3909##  ##STR3910## 1.97 525.2991 526.2742  1084 ##STR3911## ##STR3912##  ##STR3913## ##STR3914##  ##STR3915## 1.98 525.2991 529.2836 1085 ##STR3916## ##STR3917##  ##STR3918## ##STR3919##  ##STR3920## 1.82 588.3134 589.3152  1086 ##STR3921## ##STR3922##  ##STR3923## ##STR3924##  ##STR3925## 1.93 511.3199 512.2905  1087 ##STR3926## ##STR3927##  ##STR3928## ##STR3929##  ##STR3930## 2.06
565.2496 566.2386  1088 ##STR3931## ##STR3932##  ##STR3933## ##STR3934##  ##STR3935## 2.07 559.2835 560.2629  1089 ##STR3936## ##STR3937##  ##STR3938## ##STR3939##  ##STR3940## 1.99 559.2835 560.2698  1090 ##STR3941## ##STR3942##  ##STR3943## ##STR3944## ##STR3945## 2.02 628.3447 629.3398  1091 ##STR3946## ##STR3947##  ##STR3948## ##STR3949##  ##STR3950## 2 593.2348 594.2117  1092 ##STR3951## ##STR3952##  ##STR3953## ##STR3954##  ##STR3955## 1.95 559.2835 560.2643  1093 ##STR3956## ##STR3957## 
##STR3958## ##STR3959##  ##STR3960## 2.02 593.2445 594.2274  1094 ##STR3961## ##STR3962##  ##STR3963## ##STR3964##  ##STR3965## 2.03 573.2991 574.271  1095 ##STR3966## ##STR3967##  ##STR3968## ##STR3969##  ##STR3970## 1.71 607.2617 608.2644  1096
##STR3971## ##STR3972##  ##STR3973## ##STR3974##  ##STR3975## 2.11 629.3254 630.3112  1097 ##STR3976## ##STR3977##  ##STR3978## ##STR3979##  ##STR3980## 2.11 595.341 596.3187  1098 ##STR3981## ##STR3982##  ##STR3983## ##STR3984##  ##STR3985## 1.89
545.2678 546.2605  1099 ##STR3986## ##STR3987##  ##STR3988## ##STR3989##  ##STR3990## 1.96 579.2289 580.2228  1100 ##STR3991## ##STR3992##  ##STR3993## ##STR3994##  ##STR3995## 1.97 559.2835 560.2682  1101 ##STR3996## ##STR3997##  ##STR3998## ##STR3999## ##STR4000## 1.94 573.2628 574.2623  1102 ##STR4001## ##STR4002##  ##STR4003## ##STR4004##  ##STR4005## 1.83 558.3029 559.2951  1103 ##STR4006## ##STR4007##  ##STR4008## ##STR4009##  ##STR4010## 1.87 531.2886 532.2817  1104 ##STR4011## ##STR4012## 
##STR4013## ##STR4014##  ##STR4015## 1.93 565.2496 566.248  1105 ##STR4016## ##STR4017##  ##STR4018## ##STR4019##  ##STR4020## 1.95 565.3042 546.2853  1106 ##STR4021## ##STR4022##  ##STR4023## ##STR4024##  ##STR4025## 1.89 545.3042 546.2955  1107
##STR4026## ##STR4027##  ##STR4028## ##STR4029##  ##STR4030## 1.98 551.3512 552.3348  1108 ##STR4031## ##STR4032##  ##STR4033## ##STR4034##  ##STR4035## 1.83 594.2301 595.2273  1109 ##STR4036## ##STR4037##  ##STR4038## ##STR4039##  ##STR4040## 2.01
531.2653 532.2531  1110 ##STR4041## ##STR4042##  ##STR4043## ##STR4044##  ##STR4045## 1.8 497.3042 498.2937  1111 ##STR4046## ##STR4047##  ##STR4048## ##STR4049##  ##STR4050## 1.96 525.2991 526.2787  1112 ##STR4051## ##STR4052##  ##STR4053## ##STR4054## 
##STR4055## 2.04 565.2496 566.2412  1113 ##STR4056## ##STR4057##  ##STR4058## ##STR4059##  ##STR4060## 2.06 559.2835 560.2628  1114 ##STR4061## ##STR4062##  ##STR4063## ##STR4064##  ##STR4065## 1.89 594.2665 295.256  1115 ##STR4066## ##STR4067## 
##STR4068## ##STR4069##  ##STR4070## 1.97 252.2991 526.292  1116 ##STR4071## ##STR4072##  ##STR4073## ##STR4074##  ##STR4075## 1.87 260.2821 561.2739  1117 ##STR4076## ##STR4077##  ##STR4078## ##STR4079##  ##STR4080## 1.86 560.2821 561.2766  1118
##STR4081## ##STR4082##  ##STR4083## ##STR4084##  ##STR4085## 1.88 560.2821 561.2753  1119 ##STR4086## ##STR4087##  ##STR4088## ##STR4089##  ##STR4090## 1.89 524.3151 525.3075  1120 ##STR4091## ##STR4092##  ##STR4093## ##STR4094##  ##STR4095## 2 645.2839
646.274  1121 ##STR4096## ##STR4097##  ##STR4098## ##STR4099##  ##STR4100## 1.99 651.25 652.2567  1122 ##STR4101## ##STR4102##  ##STR4103## ##STR4104##  ##STR4105## 2.01 631.3049 632.2967  1123 ##STR4106## ##STR4107##  ##STR4108## ##STR4109## 
##STR4110## 1.89 644.3362 645.35  1124 ##STR4111## ##STR4112##  ##STR4113## ##STR4114##  ##STR4115## 2.01 631.2682 632.2625  1125 ##STR4116## ##STR4117##  ##STR4118## ##STR4119##  ##STR4120## 2 637.2344 638.2382  1126 ##STR4121## ##STR4122##  ##STR4123##
##STR4124##  ##STR4125## 2.01 617.289 618.2725  1127 ##STR4126## ##STR4127##  ##STR4128## ##STR4129##  ##STR4130## 1.9 630.3206 631.3359  1128 ##STR4131## ##STR4132##  ##STR4133## ##STR4134##  ##STR4135## 2.07 627.2709 628.2573  1129 ##STR4136##
##STR4137##  ##STR4138## ##STR4139##  ##STR4140## 2.02 573.2991 574.2791  1130 ##STR4141## ##STR4142##  ##STR4143## ##STR4144##  ##STR4145## 1.92 586.3307 587.3427  1131 ##STR4146## ##STR4147##  ##STR4148## ##STR4149##  ##STR4150##  1132 ##STR4151##
##STR4152##  ##STR4153## ##STR4154##  ##STR4155## 1.87 561.2991 562.3006  1133 ##STR4156## ##STR4157##  ##STR4158## ##STR4159##  ##STR4160##  1134 ##STR4161## ##STR4162##  ##STR4163## ##STR4164##  ##STR4165##  1135 ##STR4166## ##STR4167##  ##STR4168##
##STR4169##  ##STR4170##  1136 ##STR4171## ##STR4172##  ##STR4173## ##STR4174##  ##STR4175##  1137 ##STR4176## ##STR4177##  ##STR4178## ##STR4179##  ##STR4180##  1138 ##STR4181## ##STR4182##  ##STR4183## ##STR4184##  ##STR4185##  1139 ##STR4186##
##STR4187##  ##STR4188## ##STR4189##  ##STR4190##  1140 ##STR4191## ##STR4192##  ##STR4193## ##STR4194##  ##STR4195## 1.81 558.3359 559.3449  1141 ##STR4196## ##STR4197##  ##STR4198## ##STR4199##  ##STR4200## 1.96 603.2369 604.2373  1142 ##STR4201##
##STR4202##  ##STR4203## ##STR4204##  ##STR4205## 1.95 609.2031 610.2124  1143 ##STR4206## ##STR4207##  ##STR4208## ##STR4209##  ##STR4210## 2.02 613.2552 614.2456  1144 ##STR4211## ##STR4212##  ##STR4213## ##STR4214##  ##STR4215## 1.96 559.2835 560.2794 1145 ##STR4216## ##STR4217##  ##STR4218## ##STR4219##  ##STR4220## 1.86 572.3151 573.3293  1146 ##STR4221## ##STR4222##  ##STR4223## ##STR4224##


 ##STR4225## 1.98 603.2733 604.278  1147 ##STR4226## ##STR4227##  ##STR4228## ##STR4229##  ##STR4230## 2.05 575.3148 576.3073  1148 ##STR4231## ##STR4232##  ##STR4233## ##STR4234##  ##STR4235## 2.04 539.3148 540.3035  1149 ##STR4236## ##STR4237## ##STR4238## ##STR4239##  ##STR4240## 2.01 631.3046 632.2966  1150 ##STR4241## ##STR4242##  ##STR4243## ##STR4244## ##STR4245##  ##STR4246## 1.91 508.3202 509.323  1151 ##STR4247## ##STR4248##  ##STR4249## ##STR4250##  ##STR4251## 2.1 535.3563 536.3535 
1152 ##STR4252## ##STR4253##  ##STR4254## ##STR4255##  ##STR4256## 2.07 521.3406 522.3412  1153 ##STR4257## ##STR4258##  ##STR4259## ##STR4260##  ##STR4261## 1.88 511.3199 512.3171  1154 ##STR4262## ##STR4263##  ##STR4264## ##STR4265##  ##STR4266## 1.85
575.3148 576.3098  1155 ##STR4267## ##STR4268##  ##STR4269## ##STR4270## ##STR4271##  ##STR4272## 1.91 509.3406 510.3491  1156 ##STR4273## ##STR4274##  ##STR4275## ##STR4276##  ##STR4277## 1.86 495.325 496.3272


 TABLE 2A  ##STR4278##  H +  CMP  R4 is H unless otherwise specified  Rtn. Cmp. Ion  # R1 R2 R3  R4 R5 R6  Time Mass Obs  1157 ##STR4279## ##STR4280##  ##STR4281## ##STR4282##  ##STR4283## 1.98 451.2987 452.3944  1158 ##STR4284## ##STR4285## 
##STR4286## ##STR4287##  ##STR4288## 2.07 485.2831 486.3753  1159 ##STR4289## ##STR4290##  ##STR4291## ##STR4292##  ##STR4293## 2.05 515.2936 516.3962  1160 ##STR4294## ##STR4295##  ##STR4296## ##STR4297##  ##STR4298## 2.15 491.33 492.4342  1161
##STR4299## ##STR4300##  ##STR4301## ##STR4302##  ##STR4303## 2.11 529.2093 530.32  1162 ##STR4304## ##STR4305##  ##STR4306## ##STR4307##  ##STR4308## 2.11 563.1936 564.31  1163 ##STR4309## ##STR4310##  ##STR4311## ##STR4312##  ##STR4313## 2.11 593.2042
594.33  1164 ##STR4314## ##STR4315##  ##STR4316## ##STR4317##  ##STR4318##  1165 ##STR4319## ##STR4320##  ##STR4321## ##STR4322##  ##STR4323## 2.05 469.2893 470.3595  1166 ##STR4324## ##STR4325##  ##STR4326## ##STR4327##  ##STR4328## 2.06 503.2737
504.3713  1167 ##STR4329## ##STR4330##  ##STR4331## ##STR4332##  ##STR4333## 2.05 533.2442 534.3885  1168 ##STR4334## ##STR4335##  ##STR4336## ##STR4337##  ##STR4338## 2.15 504.3206 510.9258  1169 ##STR4339## ##STR4340##  ##STR4341## ##STR4342## 
##STR4343## 2.10 485.2578 486.3618  1170 ##STR4344## ##STR4345##  ##STR4346## ##STR4347##  ##STR4348## 2.09 579.2441 520.3508  1171 ##STR4349## ##STR4350##  ##STR4351## ##STR4352##  ##STR4353## 2.10 549.2547 550.3768  1172 ##STR4354## ##STR4355## 
##STR4356## ##STR4357##  ##STR4358## 2.18 525.2911 526.4115  1173 ##STR4359## ##STR4360##  ##STR4361## ##STR4362##  ##STR4363## 2.06 465.3144 466.4148  1174 ##STR4364## ##STR4365##  ##STR4366## ##STR4367##  ##STR4368## 2.10 499.2987 500.4062  1175
##STR4369## ##STR4370##  ##STR4371## ##STR4372##  ##STR4373## 2.10 529.3093 530.4219  1176 ##STR4374## ##STR4375##  ##STR4376## ##STR4377##  ##STR4378##  1177 ##STR4379## ##STR4380##  ##STR4381## ##STR4382##  ##STR4383## 1.86 481.3093 482.4177  1178
##STR4384## ##STR4385##  ##STR4386## ##STR4387##  ##STR4388## 2.07 515.2036 516.4023  1179 ##STR4389## ##STR4390##  ##STR4391## ##STR4392##  ##STR4393## 2.06 545.3042 546.4252  1180 ##STR4394## ##STR4395##  ##STR4396## ##STR4397##  ##STR4398## 2.12
621.3408 622.4584  1181 ##STR4399## ##STR4400##  ##STR4401## ##STR4402##  ##STR4403## 2.11 619.2881 520.4012  1182 ##STR4404## ##STR4405##  ##STR4406## ##STR4407##  ##STR4408## 2.09 553.2705 554.3881  1183 ##STR4409## ##STR4410##  ##STR4411## ##STR4412## ##STR4413## 2.1 583.2811 584.4048  1184 ##STR4414## ##STR4415##  ##STR4416## ##STR4417##  ##STR4418## 2.17 559.3174 560.4424  1185 ##STR4419## ##STR4420##  ##STR4421## ##STR4422##  ##STR4423## 1.95 495.325 496.4399  1186 ##STR4424## ##STR4425## 
##STR4426## ##STR4427##  ##STR4428## 2.11 529.3093 530.4105  1187 ##STR4429## ##STR4430##  ##STR4431## ##STR4432##  ##STR4433## 2.09 559.3199 560.4452  1188 ##STR4434## ##STR4435##  ##STR4436## ##STR4437##  ##STR4438##  1189 ##STR4439## ##STR4440## 
##STR4441## ##STR4442##  ##STR4443## 2.15 519.2208 520.3397  1190 ##STR4444## ##STR4445##  ##STR4446## ##STR4447##  ##STR4448## 2.15 553.2051 554.3284  1191 ##STR4449## ##STR4450##  ##STR4451## ##STR4452##  ##STR4453## 2.26 559.2521 560.3608  1192
##STR4454## ##STR4455##  ##STR4456## ##STR4457##  ##STR4458## 1.85 511.3199 512.4327  1193 ##STR4459## ##STR4460##  ##STR4461## ##STR4462##  ##STR4463## 2.05 545.3042 546.4219  1194 ##STR4464## ##STR4465##  ##STR4466## ##STR4467##  ##STR4468## 2.04
575.3148 576.4352  1195 ##STR4469## ##STR4470##  ##STR4471## ##STR4472##  ##STR4473## 2.09 551.3512 552.4758  1196 ##STR4474## ##STR4475##  ##STR4476## ##STR4477##  ##STR4478## 1.91 511.3199 512.4281  1197 ##STR4479## ##STR4480##  ##STR4481## ##STR4482## ##STR4483## 2.05 545.3042 546.4178  1198 ##STR4484## ##STR4485##  ##STR4486## ##STR4487##  ##STR4488## 2.05 575.3148 576.4329  1199 ##STR4489## ##STR4490##  ##STR4491## ##STR4492##  ##STR4493## 2.12 551.3512 552.4684  1200 ##STR4494## ##STR4495## 
##STR4496## ##STR4497##  ##STR4498## 2.09 529.2093 530.33  1201 ##STR4499## ##STR4500##  ##STR4501## ##STR4502##  ##STR4503## 2.11 563.1936 564.32  1202 ##STR4504## ##STR4505##  ##STR4506## ##STR4507##  ##STR4508## 2.11 593.2042 594.34  1203 ##STR4509##
##STR4510##  ##STR4511## ##STR4512##  ##STR4513##  1204 ##STR4514## ##STR4515##  ##STR4516## ##STR4517##  ##STR4518## 2 469.2893 470.3277  1205 ##STR4519## ##STR4520##  ##STR4521## ##STR4522##  ##STR4523## 2.05 503.2737 504.3181  1206 ##STR4524##
##STR4525##  ##STR4526## ##STR4527##  ##STR4528## 2.14 509.3206 510.3687  1207 ##STR4529## ##STR4530##  ##STR4531## ##STR4532##  ##STR4533## 2.06 485.2598 486.3074  1208 ##STR4534## ##STR4535##  ##STR4536## ##STR4537##  ##STR4538## 2.1 519.2441 520.2955 
1209 ##STR4539## ##STR4540##  ##STR4541## ##STR4542##  ##STR4543## 2.09 549.2547 550.3127  1210 ##STR4544## ##STR4545##  ##STR4546## ##STR4547##  ##STR4548## 2.19 525.2911 526.3676  1211 ##STR4549## ##STR4550##  ##STR4551## ##STR4552##  ##STR4553## 1.99
465.3144 466.3585  1212 ##STR4554## ##STR4555##  ##STR4556## ##STR4557##  ##STR4558## 2.1 499.2987 500.3643  1213 ##STR4559## ##STR4560##  ##STR4561## ##STR4562##  ##STR4563##  1214 ##STR4564## ##STR4565##  ##STR4566## ##STR4567##  ##STR4568## 2.19
505.3457 506.4082  1215 ##STR4569## ##STR4570##  ##STR4571## ##STR4572##  ##STR4573## 2.04 479.33 480.3875  1216 ##STR4574## ##STR4575##  ##STR4576## ##STR4577##  ##STR4578## 2.13 513.3144 514.3647  1217 ##STR4579## ##STR4580##  ##STR4581## ##STR4582## 
##STR4583## 2.13 543.325 544.3829  1218 ##STR4584## ##STR4585##  ##STR4586## ##STR4587##  ##STR4588## 2.22 519.3813 520.4385  1219 ##STR4589## ##STR4590##  ##STR4591## ##STR4592##  ##STR4593## 1.91 481.3093 482.3635  1220 ##STR4594## ##STR4595## 
##STR4596## ##STR4597##  ##STR4598## 2.06 515.2936 516.3668  1221 ##STR4599## ##STR4600##  ##STR4601## ##STR4602##  ##STR4603## 2.05 545.3042 546.3696  1222 ##STR4604## ##STR4605##  ##STR4606## ##STR4607##  ##STR4608## 2.13 521.3406 522.4055  1223
##STR4609## ##STR4610##  ##STR4611## ##STR4612##  ##STR4613## 1.97 495.325 496.3876  1224 ##STR4614## ##STR4615##  ##STR4616## ##STR4617##  ##STR4618## 2.09 529.3093 530.3716  1225 ##STR4619## ##STR4620##  ##STR4621## ##STR4622##  ##STR4623## 2.08
559.3199 560.3892  1226 ##STR4624## ##STR4625##  ##STR4626## ##STR4627##  ##STR4628## 2.17 535.3563 536.4433  1227 ##STR4629## ##STR4630##  ##STR4631## ##STR4632##  ##STR4633## 2.06 523.3563 524.4395  1228 ##STR4634## ##STR4635##  ##STR4636## ##STR4637## ##STR4638## 2.17 557.3406 558.4227  1229 ##STR4639## ##STR4640##  ##STR4641## ##STR4642##  ##STR4643## 2.16 587.3512 588.4426  1230 ##STR4644## ##STR4645##  ##STR4646## ##STR4647##  ##STR4648## 2.26 563.3876 564.4906  1231 ##STR4649## ##STR4650## 
##STR4651## ##STR4652##  ##STR4653## 2.08 519.2861 520.3691  1232 ##STR4654## ##STR4655##  ##STR4656## ##STR4657##  ##STR4658## 2.09 553.2705 554.355  1233 ##STR4659## ##STR4660##  ##STR4661## ##STR4662##  ##STR4663## 2.08 583.2811 584.3691  1234
##STR4664## ##STR4665##  ##STR4666## ##STR4667##  ##STR4668## 2.17 559.3174 560.4126  1235 ##STR4669## ##STR4670##  ##STR4671## ##STR4672##  ##STR4673## 2.07 493.3457 494.4268  1236 ##STR4674## ##STR4675##


 ##STR4676## ##STR4677##  ##STR4678## 2.17 527.3301 528.4103  1237 ##STR4679## ##STR4680##  ##STR4681## ##STR4682##  ##STR4683## 2.15 557.3406 558.4276  1238 ##STR4684## ##STR4685##  ##STR4686## ##STR4687##  ##STR4688##  1239 ##STR4689##
##STR4690##  ##STR4691## ##STR4692##  ##STR4693## 2.11 527.3301 528.4191  1240 ##STR4694## ##STR4695##  ##STR4696## ##STR4697##  ##STR4698## 2.16 561.3144 562.409  1241 ##STR4699## ##STR4700##  ##STR4701## ##STR4702##  ##STR4703## 2.15 591.325 592.4272 
1242 ##STR4704## ##STR4705##  ##STR4706## ##STR4707##  ##STR4708## 2.26 567.3613 568.463  1243 ##STR4709## ##STR4710##  ##STR4711## ##STR4712##  ##STR4713## 1.94 495.2886 496.3611  1244 ##STR4714## ##STR4715##  ##STR4716## ##STR4717##  ##STR4718## 2.05
529.2729 530.3501  1245 ##STR4719## ##STR4720##  ##STR4721## ##STR4722##  ##STR4723## 2.04 559.2835 560.3697  1246 ##STR4724## ##STR4725##  ##STR4726## ##STR4727##  ##STR4728## 2.13 535.3199 536.4042  1247 ##STR4729## ##STR4730##  ##STR4731## ##STR4732## ##STR4733## 1.94 509.3042 510.3796  1248 ##STR4734## ##STR4735##  ##STR4736## ##STR4737##  ##STR4738## 2.05 543.2886 544.3738  1249 ##STR4739## ##STR4740##  ##STR4741## ##STR4742##  ##STR4743## 2.04 573.2991 574.3901  1250 ##STR4744## ##STR4745## 
##STR4746## ##STR4747##  ##STR4748## 2.13 549.3355 550.4245  1251 ##STR4749## ##STR4750##  ##STR4751## ##STR4752##  ##STR4753## 2.1 543.325 544.4181  1252 ##STR4754## ##STR4755##  ##STR4756## ##STR4757##  ##STR4758## 2.24 583.3563 584.4531  1253
##STR4759## ##STR4760##  ##STR4761## ##STR4762##  ##STR4763## 1.82 541.3304 542.4101  1254 ##STR4764## ##STR4765##  ##STR4766## ##STR4767##  ##STR4768## 2.02 575.3148 576.4094  1255 ##STR4769## ##STR4770##  ##STR4771## ##STR4772##  ##STR4773## 1.97
605.3254 606.4261  1256 ##STR4774## ##STR4775##  ##STR4776## ##STR4777##  ##STR4778## 2 581.3618 582.4799  1257 ##STR4779## ##STR4780##  ##STR4781## ##STR4782##  ##STR4783## 2.25 597.3719 598.4869  1258 ##STR4784## ##STR4785##  ##STR4786## ##STR4787## 
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521.2643 522.3353  1319 ##STR5089## ##STR5090##  ##STR5091## ##STR5092##  ##STR5093## 2.06 551.2748 552.3566


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481.3093 482.3853  1385 ##STR5419## ##STR5420##  ##STR5421## ##STR5422##  ##STR5423## 2.04 491.2548 492.3256  1386 ##STR5424## ##STR5425##  ##STR5426## ##STR5427##  ##STR5428## 2.07 505.2705 506.3494  1387 ##STR5429## ##STR5430##  ##STR5431## ##STR5432## ##STR5433## 2.11 519.2861 520.37  1388 ##STR5434## ##STR5435##  ##STR5436## ##STR5437##  ##STR5438## 1.84 467.2937 468.3647  1389 ##STR5439## ##STR5440##  ##STR5441## ##STR5442##  ##STR5443## 1.91 481.3093 482.3842  1390 ##STR5444## ##STR5445## 
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470.2896  1429 ##STR5639## ##STR5640##  ##STR5641## ##STR5642##  ##STR5643## 1.96 457.2285 458.2379  1430 ##STR5644## ##STR5645##  ##STR5646## ##STR5647##  ##STR5648## 2.03 471.2441 472.2611  1431 ##STR5649## ##STR5650##  ##STR5651## ##STR5652## 
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##STR6696## ##STR6697##  ##STR6698## 1.82 481.3093 482.3608  1641 ##STR6699## ##STR6700##  ##STR6701## ##STR6702##  ##STR6703##  1642 ##STR6704## ##STR6705##  ##STR6706## ##STR6707##  ##STR6708## 1.73 439.2624 440.3095  1643 ##STR6709## ##STR6710## 
##STR6711## ##STR6712##  ##STR6713## 1.77 453.278 454.3231  1644 ##STR6714## ##STR6715##  ##STR6716## ##STR6717##  ##STR6718## 1.81 467.2937 468.3407  1645 ##STR6719## ##STR6720##  ##STR6721## ##STR6722##  ##STR6723## 1.88 495.325 496.385  1646
##STR6724## ##STR6725##  ##STR6726## ##STR6727##  ##STR6728## 2.11 563.1703 564.29  1647 ##STR6729## ##STR6730##  ##STR6731## ##STR6732##  ##STR6733##  1648 ##STR6734## ##STR6735##  ##STR6736## ##STR6737##  ##STR6738## 2.06 499.2999 500.3384  1649
##STR6739## ##STR6740##  ##STR6741## ##STR6742##  ##STR6743##  1650 ##STR6744## ##STR6745##  ##STR6746## ##STR6747##  ##STR6748## 2.16 553.1818 554.31  1651 ##STR6749## ##STR6750##  ##STR6751## ##STR6752##  ##STR6753##  1652 ##STR6754## ##STR6755## 
##STR6756## ##STR6757##  ##STR6758## 2.01 495.325 496.3744  1653 ##STR6759## ##STR6760##  ##STR6761## ##STR6762##  ##STR6763##  1654 ##STR6764## ##STR6765##  ##STR6766## ##STR6767##


 ##STR6768## 2 499.2999 500.344  1655 ##STR6769## ##STR6770##  ##STR6771## ##STR6772##  ##STR6773##  1656 ##STR6774## ##STR6775##  ##STR6776## ##STR6777##  ##STR6778## 2 511.3199 512.3674  1657 ##STR6779## ##STR6780##  ##STR6781## ##STR6782## 
##STR6783##  1658 ##STR6784## ##STR6785##  ##STR6786## ##STR6787##  ##STR6788##  1659 ##STR6789## ##STR6790##  ##STR6791## ##STR6792##  ##STR6793##  1660 ##STR6794## ##STR6795##  ##STR6796## ##STR6797##  ##STR6798##  1661 ##STR6799## ##STR6800## 
##STR6801## ##STR6802##  ##STR6803## 1.99 495.325 496.3893  1662 ##STR6804## ##STR6805##  ##STR6806## ##STR6807##  ##STR6808##  1663 ##STR6809## ##STR6810##  ##STR6811## ##STR6812##  ##STR6813## 2.04 509.3406 510.4029  1664 ##STR6814## ##STR6815## 
##STR6816## ##STR6817##  ##STR6818##  1665 ##STR6819## ##STR6820##  ##STR6821## ##STR6822##  ##STR6823## 1.92 511.3199 512.3715  1666 ##STR6824## ##STR6825##  ##STR6826## ##STR6827##  ##STR6828##  1667 ##STR6829## ##STR6830##  ##STR6831## ##STR6832## 
##STR6833## 1.96 525.3355 526.388  1668 ##STR6834## ##STR6835##  ##STR6836## ##STR6837##  ##STR6838##  1669 ##STR6839## ##STR6840##  ##STR6841## ##STR6842##  ##STR6843## 2.06 553.3668 554.4324  1670 ##STR6844## ##STR6845##  ##STR6846## ##STR6847## 
##STR6848##  1671 ##STR6849## ##STR6850##  ##STR6851## ##STR6852##  ##STR6853##  1672 ##STR6854## ##STR6855##  ##STR6856## ##STR6857##  ##STR6858## 2.08 523.3563 524.4255  1673 ##STR6859## ##STR6860##  ##STR6861## ##STR6862##  ##STR6863##  1674
##STR6864## ##STR6865##  ##STR6866## ##STR6867##  ##STR6868## 1.98 513.2792 514.3397  1675 ##STR6869## ##STR6870##  ##STR6871## ##STR6872##  ##STR6873##  1676 ##STR6874## ##STR6875##  ##STR6876## ##STR6877##  ##STR6878## 1.95 525.2991 526.3698  1677
##STR6879## ##STR6880##  ##STR6881## ##STR6882##  ##STR6883##  1678 ##STR6884## ##STR6885##  ##STR6886## ##STR6887##  ##STR6888## 1.97 527.2948 528.3601  1679 ##STR6889## ##STR6890##  ##STR6891## ##STR6892##  ##STR6893##  1680 ##STR6894## ##STR6895## 
##STR6896## ##STR6897##  ##STR6898## 1.95 539.3148 540.3774  1681 ##STR6899## ##STR6900##  ##STR6901## ##STR6902##  ##STR6903##  1682 ##STR6904## ##STR6905##  ##STR6906## ##STR6907##  ##STR6908##  1683 ##STR6909## ##STR6910##  ##STR6911## ##STR6912## 
##STR6913##  1684 ##STR6914## ##STR6915##  ##STR6916## ##STR6917##  ##STR6918##  1685 ##STR6919## ##STR6920##  ##STR6921## ##STR6922##  ##STR6923##  1686 ##STR6924## ##STR6925##  ##STR6926## ##STR6927##  ##STR6928## 1.91 541.3304 542.3954  1687
##STR6929## ##STR6930##  ##STR6931## ##STR6932##  ##STR6933## 1.89 529.3105 530.3705  1688 ##STR6934## ##STR6935##  ##STR6936## ##STR6937##  ##STR6938##  1689 ##STR6939## ##STR6940##  ##STR6941## ##STR6942##  ##STR6943##  1690 ##STR6944## ##STR6945## 
##STR6946## ##STR6947##  ##STR6948##  1691 ##STR6949## ##STR6950##  ##STR6951## ##STR6952##  ##STR6953## 2.03 556.3049 557.3685  1692 ##STR6954## ##STR6955##  ##STR6956## ##STR6957##  ##STR6958##  1693 ##STR6959## ##STR6960##  ##STR6961## ##STR6962## 
##STR6963##  1694 ##STR6964## ##STR6965##  ##STR6966## ##STR6967##  ##STR6968##  1695 ##STR6969## ##STR6970##  ##STR6971## ##STR6972##  ##STR6973## 2.15 553.1818 554.32  1696 ##STR6974## ##STR6975##  ##STR6976## ##STR6977##  ##STR6978##  1697 ##STR6979##
##STR6980##  ##STR6981## ##STR6982##  ##STR6983## 2.15 553.1818 554.31  1698 ##STR6984## ##STR6985##  ##STR6986## ##STR6987##  ##STR6988##  1699 ##STR6989## ##STR6990##  ##STR6991## ##STR6992##  ##STR6993## 2.09 505.2705 506.3293  1700 ##STR6994##
##STR6995##  ##STR6996## ##STR6997##  ##STR6998##  1701 ##STR6999## ##STR7000##  ##STR7001## ##STR7002##  ##STR7003##  1702 ##STR7004## ##STR7005##  ##STR7006## ##STR7007##  ##STR7008##  1703 ##STR7009## ##STR7010##  ##STR7011## ##STR7012##  ##STR7013##
1.97 609.1758 608.2943  1704 ##STR7014## ##STR7015##  ##STR7016## ##STR7017##  ##STR7018## 1.95 499.2999 500.3528  1705 ##STR7019## ##STR7020##  ##STR7021## ##STR7022##  ##STR7023##  1706 ##STR7024## ##STR7025##  ##STR7026## ##STR7027##  ##STR7028## 
1707 ##STR7029## ##STR7030##  ##STR7031## ##STR7032##  ##STR7033##  1708 ##STR7034## ##STR7035##  ##STR7036## ##STR7037##  ##STR7038## 1.87 529.3105 530.3679  1709 ##STR7039## ##STR7040##  ##STR7041## ##STR7042##  ##STR7043##  1710 ##STR7044##
##STR7045##  ##STR7046## ##STR7047##  ##STR7048## 1.89 513.3156 514.3675  1711 ##STR7049## ##STR7050##  ##STR7051## ##STR7052##  ##STR7053##  1712 ##STR7054## ##STR7055##  ##STR7056## ##STR7057##  ##STR7058## 1.86 525.3355 526.3887  1713 ##STR7059##
##STR7060##  ##STR7061## ##STR7062##  ##STR7063##  1714 ##STR7064## ##STR7065##  ##STR7066## ##STR7067##  ##STR7068## 1.88 499.2999 500.3582  1715 ##STR7069## ##STR7070##  ##STR7071## ##STR7072##  ##STR7073##  1716 ##STR7074## ##STR7075##  ##STR7076##
##STR7077##  ##STR7078## 1.83 511.3199 512.3775  1717 ##STR7079## ##STR7080##  ##STR7081## ##STR7082##  ##STR7083##  1718 ##STR7084## ##STR7085##  ##STR7086## ##STR7087##  ##STR7088##  1719 ##STR7089## ##STR7090##  ##STR7091## ##STR7092##  ##STR7093##
1.91 485.2842 486.3395  1720 ##STR7094## ##STR7095##  ##STR7096## ##STR7097##  ##STR7098##  1721 ##STR7099## ##STR7100##  ##STR7101## ##STR7102##  ##STR7103## 1.89 497.3042 498.3563  1722 ##STR7104## ##STR7105##  ##STR7106## ##STR7107##  ##STR7108## 
1723 ##STR7109## ##STR7110##  ##STR7111## ##STR7112##  ##STR7113## 1.86 515.2948 516.3523  1724 ##STR7114## ##STR7115##  ##STR7116## ##STR7117##  ##STR7118##  1725 ##STR7119## ##STR7120##  ##STR7121## ##STR7122##  ##STR7123## 1.83 486.2842 486.3419  1726
##STR7124## ##STR7125##  ##STR7126## ##STR7127##  ##STR7128## 1.8 497.3042 498.3629  1727 ##STR7129## ##STR7130##  ##STR7131## ##STR7132##  ##STR7133##  1728 ##STR7134## ##STR7135##  ##STR7136## ##STR7137##  ##STR7138## 1.83 515.2948 516.3555  1729
##STR7139## ##STR7140##  ##STR7141## ##STR7142##  ##STR7143##  1730 ##STR7144## ##STR7145##  ##STR7146## ##STR7147##  ##STR7148## 2.04 519.2452 520.3127  1731 ##STR7149## ##STR7150##  ##STR7151## ##STR7152##  ##STR7153##  1732 ##STR7154## ##STR7155## 
##STR7156## ##STR7157##  ##STR7158##  1733 ##STR7159## ##STR7160##  ##STR7161## ##STR7162##  ##STR7163## 1.88 571.341 572.4042  1734 ##STR7164## ##STR7165##  ##STR7166## ##STR7167##  ##STR7168##  1735 ##STR7169## ##STR7170##  ##STR7171## ##STR7172## 
##STR7173##  1736 ##STR7174## ##STR7175##  ##STR7176## ##STR7177##  ##STR7178## 1.96 525.3355 526.3864  1737 ##STR7179## ##STR7180##  ##STR7181## ##STR7182##  ##STR7183## 1.96 543.3261 544.3817  1738 ##STR7184## ##STR7185##


 ##STR7186## ##STR7187##  ##STR7188##  1739 ##STR7189## ##STR7190##  ##STR7191## ##STR7192##  ##STR7193## 1.92 555.3461 556.3982  1740 ##STR7194## ##STR7195##  ##STR7196## ##STR7197##  ##STR7198##  1741 ##STR7199## ##STR7200##  ##STR7201##
##STR7202##  ##STR7203##  1742 ##STR7204## ##STR7205##  ##STR7206## ##STR7207##  ##STR7208##  1743 ##STR7209## ##STR7210##  ##STR7211## ##STR7212##  ##STR7213##  1744 ##STR7214## ##STR7215##  ##STR7216## ##STR7217##  ##STR7218##  1745 ##STR7219##
##STR7220##  ##STR7221## ##STR7222##  ##STR7223## 2.02 535.2811 536.3478  1746 ##STR7224## ##STR7225##  ##STR7226## ##STR7227##  ##STR7228##  1747 ##STR7229## ##STR7230##  ##STR7231## ##STR7232##  ##STR7233##  1748 ##STR7234## ##STR7235##  ##STR7236##
##STR7237##  ##STR7238##  1749 ##STR7239## ##STR7240##  ##STR7241## ##STR7242##  ##STR7243##  1750 ##STR7244## ##STR7245##  ##STR7246## ##STR7247##  ##STR7248##  1751 ##STR7249## ##STR7250##  ##STR7251## ##STR7252##  ##STR7253##  1752 ##STR7254##
##STR7255##  ##STR7256## ##STR7257##  ##STR7258##  1753 ##STR7259## ##STR7260##  ##STR7261## ##STR7262##  ##STR7263## 2.07 589.2304 590.3111  1754 ##STR7264## ##STR7265##  ##STR7266## ##STR7267##  ##STR7268## 2.04 527.3312 528.3896  1755 ##STR7269##
##STR7270##  ##STR7271## ##STR7272##  ##STR7273##  1756 ##STR7274## ##STR7275##  ##STR7276## ##STR7277##  ##STR7278## 2.02 539.3512 540.4099  1757 ##STR7279## ##STR7280##  ##STR7281## ##STR7282##  ##STR7283##  1758 ##STR7284## ##STR7285##  ##STR7286##
##STR7287##  ##STR7288## 2.1 537.3719 538.4346  1759 ##STR7289## ##STR7290##  ##STR7291## ##STR7292##  ##STR7293##


 TABLE 3  ##STR7294##  CMP # R1 R2 R3 R4 R5  Rtn. Time Cmp. Mass H + Ion Obs  1800 ##STR7295## ##STR7296## ##STR7297## ##STR7298##  ##STR7299## 1.9 531.2158 532.2805  1801 ##STR7300## ##STR7301## ##STR7302## ##STR7303##  ##STR7304##  1802
##STR7305## ##STR7306## ##STR7307## ##STR7308##  ##STR7309## 1.98 565.2132 566.2751  1803 ##STR7310## ##STR7311## ##STR7312## ##STR7313##  ##STR7314## 1.99 515.2573 516.3182  1804 ##STR7315## ##STR7316## ##STR7317## ##STR7318##  ##STR7319## 1.96 559.2471
560.3251  1805 ##STR7320## ##STR7321## ##STR7322## ##STR7323##  ##STR7324## 1.87 481.2729 482.34  1806 ##STR7325## ##STR7326## ##STR7327## ##STR7328##  ##STR7329## 2.01 521.2234 522.2883  1807 ##STR7330## ##STR7331## ##STR7332## ##STR7333##  ##STR7334##
1.91 487.239 488.3032  1808 ##STR7335## ##STR7336## ##STR7337## ##STR7338##  ##STR7339## 2.07 515.2573 516.2889


 TABLE 4  ##STR7340##  CMP  Rtn. Cmp. H +  # R1 R2 R3 and R4 R5  R6 Time Mass Ion Obs  1809 ##STR7341## ##STR7342## ##STR7343## ##STR7344##  ##STR7345## 2.04 493.2729 494.3307  1810 ##STR7346## ##STR7347## ##STR7348## ##STR7349##  ##STR7350##
2.02 499.239 500.3034  1811 ##STR7351## ##STR7352## ##STR7353## ##STR7354##  ##STR7355##  1812 ##STR7356## ##STR7357## ##STR7358## ##STR7359##  ##STR7360##  1813 ##STR7361## ##STR7362## ##STR7363## ##STR7364##  ##STR7365##  1814 ##STR7366## ##STR7367##
##STR7368## ##STR7369##  ##STR7370## 2.01 485.2234 486.3  1815 ##STR7371## ##STR7372## ##STR7373## ##STR7374##  ##STR7375##  1816 ##STR7376## ##STR7377## ##STR7378## ##STR7379##  ##STR7380##  1817 ##STR7381## ##STR7382## ##STR7383## ##STR7384## 
##STR7385## 2.05 521.3042 522.3529  1818 ##STR7386## ##STR7387## ##STR7388## ##STR7389##  ##STR7390## 2.08 493.286 494.3401  1819 ##STR7391## ##STR7392## ##STR7393## ##STR7394##  ##STR7395## 2.02 459.325 460.3719  1820 ##STR7396## ##STR7397## ##STR7398##
##STR7399##  ##STR7400## 2.01 469.325 460.3708  1821 ##STR7401## ##STR7402## ##STR7403## ##STR7404##  ##STR7405## 2.05 527.2703 628.3184  1822 ##STR7406## ##STR7407## ##STR7408## ##STR7409##  ##STR7410## 2.04 501.3355 502.3303  1823 ##STR7411##
##STR7412## ##STR7413## ##STR7414##  ##STR7415## 1.99 487.3199 488.3148


 TABLE 5  ##STR7416##  CMP # R1 R2  R3 Rtn. Time Cmp.  Mass H + Ion Obs  1832 ##STR7417## ##STR7418##  ##STR7419## 2 447.231  448.2516  1833 ##STR7420## ##STR7421##  ##STR7422## 1.91  444.2413 445.2811  1834 ##STR7423## ##STR7424##  ##STR7425## 
1835 ##STR7426## ##STR7427##  ##STR7428## 2.36  433.2042 434.2552  1836 ##STR7429## ##STR7430##  ##STR7431## 2.33  433.2042 434.2509  1837 ##STR7432## ##STR7433##  ##STR7434## 2.33  433.2042 434.2613  1838 ##STR7435## ##STR7436##  ##STR7437## 2.22 
419.1885 420.2401  1839 ##STR7438## ##STR7439##  ##STR7440## 2.3  505.2253 506.2785  1840 ##STR7441## ##STR7442##  ##STR7443## 2.31  421.2042 422.2463  1841 ##STR7444## ##STR7445##  ##STR7446## 2.2  419.1885 420.2424  1842 ##STR7447## ##STR7448## 
##STR7449## 2.27  419.1885 420.2401  1843 ##STR7450## ##STR7451##  ##STR7452## 2.32  505.2253 506.2746  1844 ##STR7453## ##STR7454##  ##STR7455## 2.3  505.2253 506.2814  1845 ##STR7456## ##STR7457##  ##STR7458## 2.27  421.1678 422.2155  1846 ##STR7459##
##STR7460##  ##STR7461## 2.4  427.1936 428.2449  1847 ##STR7462## ##STR7463##  ##STR7464## 2.33  413.1991 414.2406  1848 ##STR7465## ##STR7466##  ##STR7467## 2.25  465.1576 466.216  1849 ##STR7468## ##STR7469##  ##STR7470## 2.12  420.2202 421.262  1850
##STR7471## ##STR7472##  ##STR7473## 2.33  489.1552 490.2146  1851 ##STR7474## ##STR7475##  ##STR7476## 2.46 495.181  496.2438  1852 ##STR7477## ##STR7478##  ##STR7479## 2.37  481.1865 482.2455  1853 ##STR7480## ##STR7481##  ##STR7482## 2.17  488.2076
489.2776  1854 ##STR7483## ##STR7484##  ##STR7485## 2.4 471.181  472.2344  1855 ##STR7486## ##STR7487##  ##STR7488## 2.49  457.2042 458.2641  1856 ##STR7489## ##STR7490##  ##STR7491## 2.4  443.2097 444.2538  1857 ##STR7492## ##STR7493##  ##STR7494## 2.42 433.2042 434.2522  1858 ##STR7495## ##STR7496##  ##STR7497##  1859 ##STR7498## ##STR7499##  ##STR7500##  1860 ##STR7501## ##STR7502##  ##STR7503##  1861 ##STR7504## ##STR7505##  ##STR7506## 2.17  490.2369 491.2785  1862 ##STR7507## ##STR7508## 
##STR7509## 2.1  479.2321 480.2817  1863 ##STR7510## ##STR7511##  ##STR7512##  1864 ##STR7513## ##STR7514##  ##STR7515##  1865 ##STR7516## ##STR7517##  ##STR7518##  1866 ##STR7519## ##STR7520##  ##STR7521## 2.15  485.2027 486.248  1867 ##STR7522##
##STR7523##  ##STR7524## 2.29  472.1762 473.2223  1868 ##STR7525## ##STR7526##  ##STR7527## 1.78  411.1583 412.1952  1869 ##STR7528## ##STR7529##  ##STR7530## 2.44  443.1111 444.1614  1870 ##STR7531## ##STR7532##  ##STR7533## 2.4  423.1657 424.1971  1871
##STR7534## ##STR7535##  ##STR7536## 2.11  504.2577 505.2372  1872 ##STR7537## ##STR7538##  ##STR7539## 2.08  508.2326 509.2144  1873 ##STR7540## ##STR7541##  ##STR7542## 2.21  524.2031 525.1942  1874 ##STR7543## ##STR7544##  ##STR7545## 2.4  558.2294
559.21  1875 ##STR7546## ##STR7547##  ##STR7548## 2.01 490.242  491.2217  1876 ##STR7549## ##STR7550##  ##STR7551## 2.11  524.2031 525.1987  1877 ##STR7552## ##STR7553##  ##STR7554## 2.04  508.2326 509.2227


 TABLE 5  ##STR7555##  CMP # R1 R2  R3 Rtn. Time Cmp.  Mass H + Ion Obs  1878 ##STR7556##  ##STR7557## ##STR7558## 2.43  417.2093 418.29  1879 ##STR7559##  ##STR7560## ##STR7561## 2.42  417.2093 418.2941  1880 ##STR7562##  ##STR7563## ##STR7564##
2.4  417.2093 418.2959  1881 ##STR7565##  ##STR7566## ##STR7567## 2.35  421.1842 422.275  1882 ##STR7568##  ##STR7569## ##STR7570## 2.53  411.2562 412.3455  1883 ##STR7571##  ##STR7572## ##STR7573## 2.57  423.2562 424.3539  1884 ##STR7574##  ##STR7575##
##STR7576## 2.42  437.1546 438.1642  1885 ##STR7577##  ##STR7578## ##STR7579## 2.37  417.2093 418.2095  1886 ##STR7580##  ##STR7581## ##STR7582## 2.41  417.2093 418.2095  1887 ##STR7583##  ##STR7584## ##STR7585## 2.42  431.2249 432.2221  1888 ##STR7586## ##STR7587## ##STR7588## 2.48  517.0903 518.1107  1889 ##STR7589##  ##STR7590## ##STR7591## 2.46  429.2093 430.2187  1890 ##STR7592##  ##STR7593## ##STR7594## 2.48  429.2093 430.2192  1891 ##STR7595##  ##STR7596## ##STR7597## 2.41  433.1842 434.2012  1892
##STR7598##  ##STR7599## ##STR7600## 2.46  469.1041 470.13  1893 ##STR7601##  ##STR7602## ##STR7603## 2.21  549.1182 550.13  1894 ##STR7604##  ##STR7605## ##STR7606## 2.49  393.2126 394.2145  1895 ##STR7607##  ##STR7608## ##STR7609## 2.39  407.246
408.2388  1896 ##STR7610##  ##STR7611## ##STR7612## 2.75  477.1837 478.2005  1897 ##STR7613##  ##STR7614## ##STR7615##  1898 ##STR7616##  ##STR7617## ##STR7618## 2.6  525.1529 526.1517  1899 ##STR7619##  ##STR7620## ##STR7621## 2.47  409.2406 410.246 
1900 ##STR7622##  ##STR7623## ##STR7624## 2.58  437.2719 438.2745  1901 ##STR7625##  ##STR7626## ##STR7627## 2.38  433.2042 434.2162  1902 ##STR7628##  ##STR7629## ##STR7630## 2.44  413.2355 414.2371  1903 ##STR7631##  ##STR7632## ##STR7633## 2.42 
413.2355 414.239  1904 ##STR7634##  ##STR7635## ##STR7636## 2.39  413.2355 414.2406  1905 ##STR7637##  ##STR7638## ##STR7639## 2.27  401.1991 402.2075  1906 ##STR7640##  ##STR7641## ##STR7642## 2.28  401.1991 402.2055  1907 ##STR7643##  ##STR7644##
##STR7645## 2.3  421.1445 422.163  1908 ##STR7646##  ##STR7647## ##STR7648## 2.28  411.1446 412.1578  1909 ##STR7649##  ##STR7650## 2.47  407.246 408.2634  1910 ##STR7651##  ##STR7652## 2.45  407.246 408.2503  1911 ##STR7653##  ##STR7654## 2.46  415.2123
416.2284  1912 ##STR7655##  ##STR7656## ##STR7657## 2.16  508.2281 509.2342  1913 ##STR7658##  ##STR7659## ##STR7660## 1.99  524.2231 525.2272  1914 ##STR7661##  ##STR7662## ##STR7663## 2.19  528.1735 529.1874  1915 ##STR7664##  ##STR7665## ##STR7666##
2.38  562.1999 563.214  1916 ##STR7667##  ##STR7668##  1917 ##STR7669##  ##STR7670##  1918 ##STR7671##  ##STR7672## ##STR7673## 2.13  494.2482 495.2661  1919 ##STR7674##  ##STR7675## ##STR7676##  1920 ##STR7677##  ##STR7678## ##STR7679## 2.13  449.2216
450.2522  1921 ##STR7680##  ##STR7681## ##STR7682## 2.11  467.2121 468.2447  1922 ##STR7683##  ##STR7684## ##STR7685## 2.14  467.2121 468.2424  1923 ##STR7686##  ##STR7687## ##STR7688## 2.11  479.2321 480.2583  1924 ##STR7689##  ##STR7690## ##STR7691##
2.52  400.2515 401.2748  1925 ##STR7692##  ##STR7693## 2.52  412.2515 413.2805  1926 ##STR7694##  ##STR7695## ##STR7696## 2.28  346.2045 347.2321  1927 ##STR7697##  ##STR7698## ##STR7699## 2.25  366.1732 367.2062  1928 ##STR7700##  ##STR7701##
##STR7702## 2.11  531.3097 532.3127  1929 ##STR7703##  ##STR7704## ##STR7705## 1.96  503.2243 504.2599  1930 ##STR7706##  ##STR7707## ##STR7708## 2  517.2399 518.2693  1931 ##STR7709##  ##STR7710## ##STR7711## 1.96  519.2534 520.2534  1932 ##STR7712## 
##STR7713## ##STR7714## 2.02  505.2132 506.2226  1933 ##STR7715##  ##STR7716## ##STR7717## 2.05  529.2941 530.2949  1934 ##STR7718##  ##STR7719## ##STR7720## 2.03  529.2941 530.2936  1935 ##STR7721##  ##STR7722## ##STR7723## 1.92  531.2733 532.2859  1936
##STR7724##  ##STR7725## ##STR7726## 1.91  531.2733 532.2828  1937 ##STR7727##  ##STR7728## ##STR7729## 2.27  520.203 521.2229  1938 ##STR7730##  ##STR7731## ##STR7732## 2.25  520.203 521.2301  1939 ##STR7733##  ##STR7734## ##STR7735## 2.32  534.2186
535.2426  1940 ##STR7736##  ##STR7737## ##STR7738## 2.19  540.1695 541.1906  1941 ##STR7739##  ##STR7740## ##STR7741## 2.23  560.0978 561.14  1942 ##STR7742##  ##STR7743## ##STR7744## 2.23  560.0978 561.14  1943 ##STR7745##  ##STR7746## ##STR7747## 2.28 
574.1135 575.16  1944 ##STR7748##  ##STR7749## ##STR7750##  1945 ##STR7751##  ##STR7752## ##STR7753## 2.19  497.1982 498.2381  1946 ##STR7754##  ##STR7755## ##STR7756## 2.26  511.2139 512.2437  1947 ##STR7757##  ##STR7758## ##STR7759## 2.25  511.2139
512.2531  1948 ##STR7760##  ##STR7761## ##STR7762## 2.3  520.203 521.2333  1949 ##STR7763##  ##STR7764## ##STR7765## 2.25  497.1982 498.2341  1950 ##STR7766##  ##STR7767## ##STR7768## 2.25  497.1982 498.2305  1951 ##STR7769##  ##STR7770## ##STR7771## 2.3 511.2139 512.2459  1952 ##STR7772##  ##STR7773## ##STR7774## 2.3  511.2139 512.2452  1953 ##STR7775##  ##STR7776## ##STR7777## 2.07  504.2577 505.2828  1954 ##STR7778##  ##STR7779## ##STR7780## 2.07  504.2577 505.2755  1955 ##STR7781##  ##STR7782##
##STR7783## 2.05  508.2326 509.2624  1956 ##STR7784##  ##STR7785## ##STR7786## 2.03  520.2526 521.2831  1957 ##STR7787##  ##STR7788## ##STR7789##  1958 ##STR7790##  ##STR7791## ##STR7792## 2.05  486.2671 487.2196  1959 ##STR7793##  ##STR7794##
##STR7795## 2.06  486.2671 487.2379  1960 ##STR7796##  ##STR7797## ##STR7798## 2.02  502.262 503.2366  1961 ##STR7799##


 ##STR7800## ##STR7801## 2.55  507.098 508.09  1962 ##STR7802##  ##STR7803## ##STR7804## 2.49  449.1329 450.125  1963 ##STR7805##  ##STR7806## ##STR7807## 2.49  449.1329 450.1363  1964 ##STR7808##  ##STR7809## ##STR7810## 2.55  463.1485 464.155 
1965 ##STR7811##  ##STR7812## ##STR7813## 2.5  461.1329 462.152  1966 ##STR7814##  ##STR7815## ##STR7816## 2.13  508.115 509.1421  1967 ##STR7817##  ##STR7818## ##STR7819## 2.39  437.1546 438.191  1968 ##STR7820##  ##STR7821## ##STR7822## 2.1  520.1011
521.1198  1969 ##STR7823##  ##STR7824## ##STR7825## 2.16  486.2307 487.2447  1970 ##STR7826##  ##STR7827## ##STR7828## 2.01  424.2151 425.2368  1971 ##STR7829##  ##STR7830## ##STR7831## 2.08  472.115 473.1456  1972 ##STR7832##  ##STR7833## ##STR7834##
2.38  437.1546 438.1952  1973 ##STR7835##  ##STR7836## ##STR7837## 2.37  431.2249 432.2486  1974 ##STR7838##  ##STR7839## ##STR7840## 2.38  437.1546 438.1897  1975 ##STR7841##  ##STR7842## ##STR7843## 2.33  403.1936 404.224  1976 ##STR7844##  ##STR7845##
##STR7846## 2.36  415.1936 416.2279  1977 ##STR7847##  ##STR7848## ##STR7849## 2.3  421.1842 422.218  1978 ##STR7850##  ##STR7851## ##STR7852## 2.29  433.2042 434.2361  1979 ##STR7853##  ##STR7854## ##STR7855## 2.32  447.2198 448.251  1980 ##STR7856## 
##STR7857## ##STR7858## 1.88  547.2026 548.3105  1981 ##STR7859##  ##STR7860## ##STR7861## 1.9  549.2228 550.3254  1982 ##STR7862##  ##STR7863## ##STR7864## 1.97  525.2592 526.3528  1983 ##STR7865##  ##STR7866## ##STR7867## 1.94  577.2132 578.3243  1984
##STR7868##  ##STR7869## ##STR7870## 2.01  553.2496 554.3531  1985 ##STR7871##  ##STR7872## ##STR7873## 1.92  581.229 582.3329  1986 ##STR7874##  ##STR7875## ##STR7876## 1.95  551.1531 552.2697  1987 ##STR7877##  ##STR7878## ##STR7879## 1.95  581.1637
582.2848  1988 ##STR7880##  ##STR7881## ##STR7882## 2.03  557.2001 558.311  1989 ##STR7883##  ##STR7884## ##STR7885## 1.9  591.1522 592.27  1990 ##STR7886##  ##STR7887## ##STR7888## 2.02  617.3042 618.4236  1991 ##STR7889##  ##STR7890## ##STR7891## 1.92 
639.1383 640.2621  1992 ##STR7892##  ##STR7893## ##STR7894## 1.95  607.2238 608.3556  1993 ##STR7895##  ##STR7896## ##STR7897## 1.92  621.1627 622.29  1994 ##STR7898##  ##STR7899## ##STR7900## 1.96  651.1733 652.31  1995 ##STR7901##  ##STR7902##
##STR7903## 1.93  657.1288 658.2678  1996 ##STR7904##  ##STR7905## ##STR7906## 1.95  605.1678 606.29  1997 ##STR7907##  ##STR7908## ##STR7909## 2.02  581.2042 582.32  1998 ##STR7910##  ##STR7911## ##STR7912## 1.96  593.1904 594.3127  1999 ##STR7913## 
##STR7914## ##STR7915## 1.97  615.1901 616.3185  2000 ##STR7916##  ##STR7917## ##STR7918## 2.04  591.2264 592.3466  2001 ##STR7919##  ##STR7920## ##STR7921## 1.93  578.2682 579.3848  2002 ##STR7922##  ##STR7923##  2003 ##STR7924##  ##STR7925##  2004
##STR7926##  ##STR7927##  2005 ##STR7928##  ##STR7929##  2006 ##STR7930##  ##STR7931## ##STR7932## 2.47  475.2511 476.2856  2007 ##STR7933##  ##STR7934## ##STR7935## 2.36  403.1936 404.2317  2008 ##STR7936##  ##STR7937## ##STR7938## 2.42  427.1936
428.2387  2009 ##STR7939##  ##STR7940## ##STR7941## 2.43  437.1546 438.2044  2010 ##STR7942##  ##STR7943## ##STR7944## 2.39  433.15 434.1996  2011 ##STR7945##  ##STR7946## ##STR7947## 2.39  445.1842 446.226  2012 ##STR7948##  ##STR7949## ##STR7950## 2.41 455.1452 456.196  2013 ##STR7951##  ##STR7952## ##STR7953## 2.41  433.15 434.1984  2014 ##STR7954##  ##STR7955## ##STR7956## 2.42  443.1111 444.1632  2015 ##STR7957##  ##STR7958## ##STR7959## 2.47  443.1111 444.1649  2016 ##STR7960##  ##STR7961##
##STR7962## 2.53  477.0721 478.137  2017 ##STR7963##  ##STR7964## ##STR7965## 2.41  423.1657 424.2055


 TABLE 6  ##STR7966##  R1 or  Rtn. Cmp. H +  CMP # R1 and R2 R3 R4 R5  R6 time Mass Ion Obs  1824 ##STR7967## ##STR7968## ##STR7969## ##STR7970##  1.91 424.2151 425.2364  1825 ##STR7971## ##STR7972## ##STR7973## ##STR7974##  ##STR7975## 2.17
558.2518 559.2742  1826 ##STR7976## ##STR7977## ##STR7978## ##STR7979##  ##STR7980## 2.2 514.262 515.286  1827 ##STR7981## ##STR7982## ##STR7983##  ##STR7984## 2.09 508.2362 509.2629  1828 ##STR7985## ##STR7986## ##STR7987##  ##STR7988## 2.1 464.2464
465.2729  1829 ##STR7989## ##STR7990## ##STR7991##  ##STR7992## 2.04 514.2023 515.2661  1830 ##STR7993## ##STR7994## ##STR7995##  ##STR7996## 1.98 436.2281 437.2896  1831 ##STR7997## ##STR7998## ##STR7999##  ##STR8000## 2.06 470.2126 471.2746


* * * * *























				
DOCUMENT INFO
Description: BACKGROUND1. Field of the InventionThis invention relates to low molecular weight, non-peptidic, non-peptidomimetic, organic molecules that act as modulators of mammalian complement C5a receptors, preferably ones that act as high affinity C5a recptor ligands. The invention alsorelates to such ligands that act as antagonists (including inverse agonists) of complement C5a receptors, preferably human C5a receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to theuse of such compounds in treating a variety of inflammatory and immune system disorders. Additionally, this invention relates to the use such compounds as probes for the localization of C5a receptors.2. Background of the InventionC5a, a 74 amino acid peptide, is generated in the complement cascade by the cleavage of the complement protein C5 by the complement C5 convertase enzyme. C5a has both anaphylatoxic (e.g., bronchoconstricting and vascular spasmogenic) andchemotactic effects. Therefore, it is active in engendering both the vascular and cellular phases of inflammatory responses. Because it is a plasma protein and, therefore, generally almost instantly available at a site of an inciting stimulus, it is akey mediator in terms of initiating the complex series of events that results in augmentation and amplification of an initial inflammatory stimulus. The anaphylatoxic and chemotactic effects of the C5a peptide are believed to be mediated through itsinteration with the C5a receptor (CD88 antigen), a 52 kD membrane bound G-protein coupled receptor (GPCR). C5a is a potent chemoattractant for polymorphonuclear leukocytes, bringing neutrophils, basophils, eosinophils and monocytes to sites ofinflammation and/or cellular injury. C5a is one of the most potent chemotactic agents known for a wide variety of inflammatory cell types. C5a also "primes" or prepares neutrophils for various antibacterial functions, e.g., phagocytosis. Additionall